GCN2 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/623,312, filed Jan. 29, 2018, the contentof which is incorporated herein in its entirety by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibiting General amino acid Control Non-derepressible 2 kinase(“GCN2”). The invention also provides pharmaceutically acceptablecompositions comprising compounds of the present invention and methodsof using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

GCN2 (General amino acid Control Non-derepressible 2) is a ubiquitouslyexpressed protein kinase involved in cellular responses to amino aciddeficiency across eukaryotes (Castilho et al., 2014). Cellulardeficiency in one or more amino acids causes the accumulation ofuncharged cognate transfer RNAs (tRNAs), which are bound directly byGCN2, leading to kinase activation and phosphorylation of eukaryoticinitiation factor 2 α (eIF2α) on Serine 51 (Wek et al., 1989; Dong etal., 2000). Phosphorylation of eIF2α results in initiation of proteintranslation, which causes a reduction in the translation of most mRNAsleading to reduced global utilization of amino acids. Simultaneously,eIF2α phosphorylation increases the translation of a specific subset ofmRNAs containing certain upstream open reading frames in their 5′untranslated regions (5′-UTRs), such as the transcription factor ATF4 inmammals (Vattem and Wek, 2004), which promotes restoration of proteinhomeostasis. GCN2 is therefore a critical determinant of cell fate inresponse to amino acid depletion.

Induction of cellular responses to amino acid deficiency is emerging asan important mechanism for regulation of the mammalian immune system,particularly in certain disease settings including cancer andautoimmunity. Various immunosuppressive cell types implicated in thecontrol of immune responses in these settings, including tolerogenicdendritic cells, myeloid derived suppressor cells (MDSCs),tolerogenic/M2 macrophages and cancer cells themselves, have each beenreported to use the depletion of amino acids to suppress T-cellresponses (Munn et al., 2004; Munn et al., 2005; Rodriguez et al., 2010;Whyte et al., 2011; Uyttenhove et al., 2003). This is achieved by theintracellular transport of amino acids coupled with the overexpressionof amino acid catabolizing enzymes in these cells, such as thetryptophan catabolizing enzymes indoleamine 2,3 dioxygenase (IDO) andtryptophan 2,3 dioxygenase (TDO), and the arginine catabolizing enzymesarginase 1 and 2 (ARG1, ARG2). As a result, these cells can reduce thelocal extracellular concentrations of specific amino acids wherever theyreside, and therefore induce GCN2 activity in nearby T-cells in anantigen-specific manner (Munn et al., 2004). In the mouse system both invitro and in vivo, the depletion of local tryptophan or arginineconcentrations, for example by IDO- or ARG1-expressing dendritic cells,has been reported to induce proliferative arrest and anergy in T-cellsin a GCN2-dependent manner (Munn et al., 2005; Rodriguez et al., 2007;Fletcher et al., 2015). In addition, the induction and/or maintenance ofMDSCs and immunosuppressive regulatory T-cells (T-regs) may also bedependent on GCN2 activity under amino acid depleted conditions(Fletcher et al., 2015; Fallarino et al., 2006). Finally, other workimplicates the activation of GCN2 by IDO within tolerogenic macrophagesas a key mechanism for suppressing systemic autoimmune responses toapoptotic cells (Ravishankar et al., 2015). These findings identify GCN2as a potentially key effector of the immunosuppressive effects of aminoacid depletion associated with various disease states.

Incipient cancers need to evade host anti-cancer immunity in order tothrive (Corthay, 2014). This can be achieved by modulating tumor antigenpresentation and/or by using tumor immune evasion mechanisms to activelysuppress immune attack. High expression of amino acid catabolisingenzymes such as IDO and ARG1 has been observed across a large proportionof cancer patients with various tumor types, both in the cancer cellsthemselves and in immunosuppressive host cell types that accumulate intumors, tumor-draining lymph nodes and/or the peripheral circulation(Uyttenhove et al., 2003; Pilotte et al., 2012; Zea et al., 2005). Aminoacid depletion may therefore be a powerful and widespread immune evasionmechanism whereby anti-cancer immunity is restrained. Consistently,amino acid depletion in both tumors and tumor-draining lymph nodes hasbeen established as a resistance mechanism to existing immuno-oncologyagents, including checkpoint receptor blocking antibodies, in severalsyngeneic mouse tumor models (Holmgaard et al., 2013; Spranger et al.,2014). On this basis, inhibitors of IDO and TDO are now being progressedin clinical trials for cancer and inhibitors of additional amino acidcatabolases are in preclinical development. Accordingly, inhibitors ofGCN2 may also be useful for cancer treatment by disrupting the nodaleffector signal of amino acid depletion in the immune system andenabling an anti-cancer immune response. Genetic ablation of GCN2 iswell tolerated in mice under standard growth conditions (Zhang et al.,2002), and inhibitors of GCN2 may have broader utility than inhibitorsof individual amino acid catabolases because GCN2 responds to depletionof several different amino acids.

In addition, GCN2 activation and overexpression has been observed invarious human tumors compared with normal tissues (Ye et al., 2010; Wanget al., 2013). Depletion of GCN2 reduced the growth of mouse embryonicfibroblasts and human cancer cells in vitro under severe amino acid orglucose depleted conditions, and blocked the growth of human tumorxenografts in mice (Ye et al., 2010). GCN2 inhibitors may therefore havedirect anti-cancer effects due to the frequent disruption of nutrientsupply in the tumor microenvironment.

For these reasons, there is a need for the development of potent andselective inhibitors of GCN2 for the treatment of cancer, either assingle agents or in combination, for example with anti-CTLA4 andanti-PD1/PD-L1 checkpoint blocking antibodies.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of GCN2 kinase. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating GCN2 kinase. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofthe GCN2 enzyme in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new GCN2 inhibitors or otherregulators of kinases, signaling pathways, and cytokine levels in vitroor in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas inhibitors of GCN2 protein kinase. In some embodiments, a providedcompound inhibits GCN2.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:Ring A is selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, phenyl, an 8-10 memberedbicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur optionally fused to a 5-6membered aromatic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, a 7-12 membered partially unsaturatedspirocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 7-12 membered partiallyunsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 7-12 memberedpartially unsaturated bridged bicyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, orHet, wherein Het is a 4-8 membered saturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 7-12 membered saturated spirocyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 7-12 membered saturated bicyclic heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur;Ring B is

each R is independently hydrogen or an optionally substituted groupselected from C₁₋₆ aliphatic, a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, phenyl, an 8-10 memberedbicyclic aromatic carbocyclic ring, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; ortwo R groups are optionally taken together to form a bivalent C₂₋₄alkylene chain;two R groups are optionally taken together with their intervening atomsto form an optionally substituted 3-7-membered saturated or partiallyunsaturated monocyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen or sulfur;each R′ is independently hydrogen or a C₁₋₃ aliphatic group optionallysubstituted with halogen;each of R¹ is independently hydrogen, halogen, —CN, —NO₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NRS(O)₂R, —C(O)N═S(O)R₂, —NR₂, —NRC(O)R,—NRC(O)NR₂, —NRC(O)OR, —NRS(O)₂R, —NRS(O)₂NR₂, —OR, —ON(R)SO₂R, —P(O)R₂,—SR, —S(O)R, —S(O)₂R, —S(O)(NH)R, —S(O)₂N(R)₂, —S(NH₂)₂(O)OH, —N═S(O)R₂,—CH₃, —CH₂OH, —CH₂NHSO₂CH₃, —CH₃, —CH₂OH, —CH₂NHSO₂CH₃, —CD₃,—CD₂NRS(O)₂R, or R; or:two R¹ groups are optionally taken together to form ═O or ═NH; ortwo R¹ groups are optionally taken together to form a bivalent C₂₋₄alkylene chain;each of R² is independently hydrogen, halogen, —CN, —C(O)N(R′)₂, —OR′,—N(R′)₂, —S(O)₂R, —S(O)₂N(R)₂, —O-phenyl, or an optionally substitutedgroup selected from C₁₋₃ aliphatic, phenyl, 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclicheterocycle having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur;R³ is hydrogen, halogen, —CN, —OR′, —N(R′)₂, or an optionallysubstituted group selected from C₁₋₃ aliphatic, phenyl, or a 5-6membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;R⁴ is hydrogen, halogen, —CN, —OR, —N═S(O)R₂, —N(R)₂, or an optionallysubstituted group selected from C₁₋₃ aliphatic, a 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 7-12 membered saturated or partially unsaturated spirocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur;m is 0, 1, 2, 3, 4 or 5;n is 0, 1, or 2;p is 0 or 1; andq is 0 or 1.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘)₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —(CH₂)₀₋₄ S(O)(NR^(∘))R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;N(R^(∘))S(O)₂R^(∘); —N(R^(∘))S(O)(NR^(∘))R^(∘) ₂; —N(OR^(∘))R^(∘);—N═S(O)R^(∘) ₂; —N(OR^(∘))SO₂R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched alkylene) C(O)O—N(R^(∘))₂, wherein each R^(∘) may besubstituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺ (C₁₋₄alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, R^(x), of a provided compound comprises one or moredeuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits GCN2 with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a GCN2 protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and a GCN2 protein kinase, and an equivalent samplecomprising a GCN2 protein kinase, in the absence of said compound, orcomposition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered    bicyclic aromatic carbocyclic ring, a 4-8 membered partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur optionally    fused to a 5-6 membered aromatic ring having 0-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 7-12    membered partially unsaturated spirocyclic heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 7-12 membered partially unsaturated bridged    bicyclic heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic    heteroaromatic ring having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur, or    -   Het, wherein Het is a 4-8 membered saturated monocyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, a 7-12 membered saturated        spirocyclic heterocyclic ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, a 7-12        membered saturated bicyclic heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or a 7-12 membered saturated bridged bicyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;-   Ring B is

-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered    bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or    partially unsaturated monocyclic heterocyclic ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-10    membered bicyclic heteroaromatic ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; or    -   two R groups are optionally taken together to form a bivalent        C₂₋₄ alkylene chain;    -   two R groups are optionally taken together with their        intervening atoms to form an optionally substituted 3-7-membered        saturated or partially unsaturated monocyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen or        sulfur;-   each R′ is independently hydrogen or a C₁₋₃ aliphatic group    optionally substituted with halogen;-   each of R¹ is independently hydrogen, halogen, —CN, —NO₂, —C(O)R,    —C(O)OR, —C(O)NR₂, —C(O)NRS(O)₂R, —C(O)N═S(O)R₂, —NR₂, —NRC(O)R,    —NRC(O)NR₂, —NRC(O)OR, —NRS(O)₂R, —NRS(O)₂NR₂, —OR, —ON(R)SO₂R,    —P(O)R₂, —SR, —S(O)R, —S(O)₂R, —S(O)(NH)R, —S(O)₂N(R)₂,    —S(NH₂)₂(O)OH, —N═S(O)R₂, —CH₃, —CH₂OH, —CH₂NHSO₂CH₃, —CD₃,    —CD₂NRS(O)₂R, or R; or:    -   two R¹ groups are optionally taken together to form ═O or ═NH;        or    -   two R¹ groups are optionally taken together to form a bivalent        C₂₋₄ alkylene chain;-   each of R² is independently hydrogen, halogen, —CN, —C(O)N(R′)₂,    —OR′, —N(R′)₂, —S(O)₂R, —S(O)₂N(R)₂, —O-phenyl, or an optionally    substituted group selected from C₁₋₃ aliphatic, phenyl, 5-6 membered    monocyclic heteroaromatic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or 4-8 membered saturated    monocyclic heterocycle having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   R³ is hydrogen, halogen, —CN, —OR′, —N(R′)₂, or an optionally    substituted group selected from C₁₋₃ aliphatic, phenyl, or a 5-6    membered monocyclic heteroaromatic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R⁴ is hydrogen, halogen, —CN, —OR, —N═S(O)R₂, —N(R)₂, or an    optionally substituted group selected from C₁₋₃ aliphatic, a 4-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 7-12 membered saturated or partially    unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   m is 0, 1, 2, 3, 4 or 5;-   n is 0, 1, or 2;-   p is 0 or 1; and-   q is 0 or 1.

As defined above and described herein, Ring A is selected from a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8membered partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfuroptionally fused to a 5-6 membered aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 7-12 memberedpartially unsaturated spirocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a7-12 membered partially unsaturated bicyclic heterocyclic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, an8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or Het, whereinHet is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a7-12 membered saturated spirocyclic heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, a7-12 membered saturated bicyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 7-12 membered saturated bridged bicyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, Ring A isphenyl. In some embodiments, Ring A is an 8-10 membered bicyclicaromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 memberedpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfuroptionally fused to a 5-6 membered aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 7-12 membered partially unsaturated spirocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7-12membered partially unsaturated bicyclic heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring A is a 7-12 membered partially unsaturatedbridged bicyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Ring Ais a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, Ring A is Het. In some embodiments, Ring A is a 4-8membered saturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 7-12 membered saturated spirocyclicheterocyclic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7-12membered saturated bicyclic heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 7-12 membered saturated bridged bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring A is

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In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring B is

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In some embodiments, Ring B is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic, a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or two R groupsare optionally taken together to form a bivalent C₂₋₄ alkylene chain; ortwo R groups are optionally taken together with their intervening atomsto form an optionally substituted 3-7-membered saturated or partiallyunsaturated monocyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments R is hydrogen. In some embodiments R is anoptionally substituted C₁₋₆ aliphatic group. In some embodiments R is anoptionally substituted 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments R is an optionallysubstituted phenyl. In some embodiments R is an optionally substituted8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments Ris an optionally substituted 4-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments R is an optionally substituted 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments R is an optionallysubstituted 8-10 membered bicyclic heteroaromatic ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments two R groups are optionally taken together to form abivalent C₂₋₄ alkylene chain. In some embodiments two R groups areoptionally taken together with their intervening atoms to form anoptionally substituted 3-7-membered saturated or partially unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each of R¹ is independentlyhydrogen or a C₁-3 aliphatic group optionally substituted with halogen.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is a C₁₋₃aliphatic group optionally substituted with halogen.

In some embodiments, R′ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R¹ is independentlyhydrogen, halogen, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)NRS(O)₂R,—C(O)N═S(O)R₂, —NR₂, —NRC(O)R, —NRC(O)NR₂, —NRC(O)OR, —NRS(O)₂R,—NRS(O)₂NR₂, —OR, —ON(R)SO₂R, —P(O)R₂, —SR, —S(O)R, —S(O)₂R, —S(O)(NH)R,—S(O)₂N(R)₂, —S(NH₂)₂(O)OH, —N═S(O)R₂, —CH₃, —CH₂OH, —CH₂NHSO₂CH₃, —CD₃,—CD₂NRS(O)₂R, or R; or: two R¹ groups are optionally taken together toform ═O or ═NH; or two R¹ groups are optionally taken together to form abivalent C₂₋₄ alkylene chain.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is halogen.In some embodiments, R¹ is —CN. In some embodiments, R¹ is —NO₂. In someembodiments, R¹ is —C(O)R. In some embodiments, R¹ is —C(O)OR. In someembodiments, R¹ is —C(O)NR₂. In some embodiments, R¹ is —C(O)NRS(O)₂R.In some embodiments, R¹ is —C(O)N═S(O)R₂. In some embodiments, R¹ is—NR₂. In some embodiments, R¹ is —NRC(O)R. In some embodiments, R¹ is—NRC(O)NR₂. In some embodiments, R¹ is —NRC(O)OR. In some embodiments,R¹ is —NRS(O)₂R. In some embodiments, R¹ is —NRS(O)₂NR₂. In someembodiments, R¹ is —OR. In some embodiments, R¹ is —ON(R)SO₂R. In someembodiments, R¹ is —P(O)R₂. In some embodiments, R¹ is —SR. In someembodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R. In someembodiments, R¹ is —S(O)(NH)R. In some embodiments, R¹ is —S(O)₂N(R)₂.In some embodiments, R¹ is —S(NH₂)₂(O)OH. In some embodiments, R¹ is—N═S(O)R₂. In some embodiments, R¹ is —CD₃. In some embodiments, R¹ is—CD₂NRS(O)₂R. In some embodiments, R¹ is R. In some embodiments, two R¹groups are optionally taken together to form ═O or ═NH. In someembodiments, two R¹ groups are optionally taken together to form abivalent C₂₋₄ alkylene chain.

In some embodiments, R¹ is fluoro. In some embodiments, R¹ is chloro. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl. Insome embodiments, R¹ is —OH. In some embodiments, R¹ is —OCH₃. In someembodiments, R¹ is —CH₂OH. In some embodiments, R¹ is —CH₂CN. In someembodiments, R¹ is —CF₃. In some embodiments, R¹ is —CH₂NH₂. In someembodiments, R¹ is —COOH. In some embodiments, R¹ is —NH₂.

In some embodiments, two R¹ groups form ═O. In some embodiments, two R¹groups form ═NH. In some embodiments, two R¹ groups form

In some embodiments, R¹ is

In some embodiments, R¹ is

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In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R² is each of R² isindependently hydrogen, halogen, —CN, —C(O)N(R′)₂, —OR′, —N(R′)₂,—S(O)₂R, —S(O)₂N(R)₂, —O-phenyl, or an optionally substituted groupselected from C₁₋₃ aliphatic, phenyl, 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or 4-8 membered saturated monocyclicheterocycle having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R² is hydrogen. In some embodiments, R² is halogen.In some embodiments, R² is —CN. In some embodiments, R² is —C(O)N(R′)₂.In some embodiments, R² is —OR′. In some embodiments, R² is —N(R′)₂. Insome embodiments, R² is —S(O)₂R. In some embodiments, R² is —S(O)₂N(R)₂.In some embodiments, R² is —O-phenyl. In some embodiments, R² is anoptionally substituted C₁₋₃ aliphatic group. In some embodiments, R² isan optionally substituted phenyl. In some embodiments, R² is anoptionally substituted 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R² is an optionally substituted 4-8membered saturated monocyclic heterocycle having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is fluoro. In some embodiments, R² is chloro. Insome embodiments, R² is bromo. In some embodiments, R² is methyl. Insome embodiments, R² is ethyl. In some embodiments, R² is —CF₃. In someembodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined above and described herein, R³ is hydrogen, halogen, —CN,—OR′, —N(R′)₂, or an optionally substituted group selected from C₁₋₃aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In some embodiments, R³ is hydrogen. In some embodiments, R³ is halogen.In some embodiments, R³ is —CN. In some embodiments, R³ is —OR′. In someembodiments, R³ is —N(R′)₂. In some embodiments, R³ is an optionallysubstituted C₁₋₃ aliphatic group. In some embodiments, R³ is anoptionally substituted phenyl. In some embodiments, R³ is an optionallysubstituted 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, R⁴ is hydrogen, halogen, —CN,—OR, —N═S(O)R₂, —N(R)₂, or an optionally substituted group selected fromC₁₋₃ aliphatic, a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturatedor partially unsaturated spirocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is halogen.In some embodiments, R⁴ is —CN. In some embodiments, R⁴ is —OR. In someembodiments, R⁴ is —N═S(O)R₂. In some embodiments, R⁴ is —N(R)₂. In someembodiments, R⁴ is an optionally substituted C₁₋₃ aliphatic group. Insome embodiments, R⁴ is an optionally substituted 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁴ is an optionally substituted 7-12 memberedsaturated or partially unsaturated spirocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R⁴ is fluoro. In some embodiments, R⁴ is chloro. Insome embodiments, R⁴ is methyl. In some embodiments, R⁴ is —CF₃. In someembodiments, R⁴ is —OH. In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is selected from those depicted in Table 1,below.

As defined above and described herein, m is 0, 1, 2, 3, 4 or 5.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5.

In some embodiments, m is 1, 2 or 3.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, n is 0, 1, or 2.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, n is selected from those depicted in Table 1,below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1,below.

As defined above and described herein, q is 0 or 1.

In some embodiments, q is 0. In some embodiments, q is 1.

In some embodiments, q is selected from those depicted in Table 1,below.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is Het, thereby forming a compound of formulaII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,R¹, R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is Het and Ring B is

thereby forming a compound of formula

or a pharmaceutically acceptable salt thereof, wherein each of Het, R¹,R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I,

wherein Ring A is piperidinyl, piperazinyl, or morpholinyl, and Ring Bis thereby forming a compound of formula IV-a, IV-b, or IV-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, m, n, p, and q is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is Het and Ring B is

thereby forming a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein each of Het, R¹,R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is piperidinyl, piperazinyl, or morpholinyl,and Ring B is

thereby forming a compound of formula VI-a, VI-b, or VI-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, m, n, p, and q is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is Het and Ring B

thereby forming a compound of formula VII:

or a pharmaceutically acceptable salt thereof, wherein each of Het, R¹,R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is piperidinyl, piperazinyl, or morpholinyl,and Ring B is

thereby forming a compound of formula VIII-a, VIII-b, or VIII-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, m, n, p, and q is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I,

wherein Ring A is Het and Ring B is

thereby forming a compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein each of Het, R¹,R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is piperidinyl, piperazinyl, or morpholinyl,and Ring B is

thereby forming a compound of formula X-a, X-b, or X-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, m, n, p, and q is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is Het and Ring B is

thereby forming a compound of formula XI:

or a pharmaceutically acceptable salt thereof, wherein each of Het, R¹,R², R³, R⁴, m, n, p, and q is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring A is piperidinyl, piperazinyl, or morpholinyl,and Ring B is

thereby forming a compound of formula XII-a, XII-b, or XII-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, m, n, p, and q is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is —CF₃, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XIII-a, XIII-b, or XIII-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is chloro, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XIV-a, XIV-b, or XIV-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is —CHF₂, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XV-a, XV-b, or XV-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is —CF₃, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XVI-a, XVI-b, or XVI-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is chloro, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XVII-a, XVII-b, or XVII-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is —CHF₂, R³ is hydrogen,R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, or morpholinyl, andRing B is

thereby forming a compound of formula XVIII-a, XVIII-b, or XVIII-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is cyclopropyl, R³ ishydrogen, R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, ormorpholinyl, and Ring B is

thereby forming a compound of formula XIX-a, XIX-b, or XIX-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is azetidinyl, R³ ishydrogen, R⁴ is hydrogen, Ring A is piperidinyl, piperazinyl, ormorpholinyl, and Ring B is

thereby forming a compound of formula XX-a, XX-b, or XX-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

In certain embodiments, the present invention provides a compound offormula I, wherein n is 1, p is 1, q is 1, R² is

R³ is hydrogen, R⁴ is methyl, Ring A is piperidinyl, piperazinyl, ormorpholinyl, and Ring B is

thereby forming a compound of formula XXI-a, XXI-b, or XXI-c,respectively:

or a pharmaceutically acceptable salt thereof, wherein each of R¹ and mis as defined above and described in embodiments herein, both singly andin combination.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary compounds of formula I

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

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In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a complexcomprising GCN2 and an inhibitor.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group (“PG”),leaving group (“LG”), or transformation condition is depicted, one ofordinary skill in the art will appreciate that other protecting groups,leaving groups, and transformation conditions are also suitable and arecontemplated. Such groups and transformations are described in detail inMarch's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 5^(th) Edition, John Wiley & Sons,2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,the entirety of each of which is hereby incorporated herein byreference.

As used herein, the phrase “leaving group” (LG) includes, but is notlimited to, halogens (e.g. fluoride, chloride, bromide, iodide),sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate,nosylate, triflate), diazonium, and the like.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Examples ofsuitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Suitable aminoprotecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

Scheme 1:

General scheme for the preparation of compounds of formula I where RingB is a pyrimidine linked to the bicyclic core from position 2, R³ ishydrogen, R⁴ is hydrogen, p is 1, and q is 1.

In Scheme 1 above, each of Ring A, R¹, R², m and n is as defined aboveand below and in classes and subclasses as described herein.

Scheme 2:

General scheme for the preparation of compounds of formula I where RingB is a pyrimidine linked to the bicyclic core from position 2, R³ ishydrogen, R⁴ is hydrogen, n is 1, p is 1, and q is 1.

In Scheme 2 above, each of Ring A, R¹, R², and m is as defined above andbelow and in classes and subclasses as described herein.

Scheme 3:

General scheme for the preparation of compounds of formula I where RingB is a pyrimidine linked to the bicyclic core from position 2, R³ ishydrogen, R⁴ is hydrogen, p is 1, and q is 1.

In Scheme 3 above, each of Ring A, R¹, R², m and n is as defined aboveand below and in classes and subclasses as described herein.

Scheme 4: General scheme for the preparation of compounds of formula Iwhere Ring B is a pyrimidine linked to the bicyclic core from position4, R³ is hydrogen, R⁴ is hydrogen, n is 1, p is 1, and q is 1.

In Scheme 4 above, each of Ring A, R¹, R², and m is as defined above andbelow and in classes and subclasses as described herein.

One of skill in the art will appreciate that a compound of formula I maycontain one or more stereocenters, and may be present as an racemic ordiastereomeric mixture. One of skill in the art will also appreciatethat there are many methods known in the art for the separation ofisomers to obtain stereoenriched or stereopure isomers of thosecompounds, including but not limited to HPLC, chiral HPLC, fractionalcrystallization of diastereomeric salts, kinetic enzymatic resolution(e.g. by fungal-, bacterial-, or animal-derived lipases or esterases),and formation of covalent diastereomeric derivatives using anenantioenriched reagent.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. “March's Advanced OrganicChemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley &Sons, New York: 2001, the entirety of which is incorporated herein byreference. Such interconversions may require one or more of theaforementioned techniques, and certain methods for synthesizingcompounds of the invention are described below in the Exemplification.

5. Uses, Formulation and Administration

a. Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit GCN2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit GCN2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof GCN2 protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

b. Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of GCN2 kinase activity.

The activity of a compound utilized in this invention as an inhibitor ofGCN2, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity and/or the subsequent functionalconsequences, or ATPase activity of activated GCN2, or a mutant thereof.Alternate in vitro assays quantitate the ability of the inhibitor tobind to GCN2. Inhibitor binding may be measured by radiolabeling theinhibitor prior to binding, isolating the inhibitor/GCN2 complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with GCN2 bound to known radioligands. Detailedconditions for assaying a compound utilized in this invention as aninhibitor of GCN2, or a mutant thereof, are set forth in the Examplesbelow.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of one of more of GCN2 and aretherefore useful for treating one or more disorders associated withactivity of GCN2. Thus, in certain embodiments, the present inventionprovides a method for treating a GCN2-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “GCN2-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which GCN2, or a mutant thereof, are known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichGCN2, or a mutant thereof, are known to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is selected from the group consisting ofinflammatory conditions, immunological conditions, autoimmuneconditions, allergic conditions, rheumatic conditions, thromboticconditions, cancer, infections, neurodegenerative diseases, degenerativediseases, neuroinflammatory diseases, cardiovascular diseases, andmetabolic conditions.

In some embodiments, the cancer to be treated is a solid tumor or atumor of the blood and immune system.

In some embodiments, the cancer is a solid tumor, wherein the solidtumor originates from the group of tumors of the epithelium, thebladder, the stomach, the kidneys, of head and neck, the esophagus, thecervix, the thyroid, the intestine, the liver, the brain, the prostate,the uro-genital tract, the lymphatic system, the stomach, the larynx,the bones, including chondrosarcoma and Ewing sarcoma, germ cells,including embryonal tissue tumors, and/or the lung, from the group ofmonocytic leukemia, lung adenocarcinoma, small-cell lung carcinomas,pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breastcarcinoma and/or maligna melanoma.

In some embodiments, the autoimmune condition is rheumatoid arthritis,systemic lupus, multiple sclerosis, psoriasis, Sjögrens syndrome ortransplant organ rejection.

In some embodiments, the metabolic condition is diabetes.

In some embodiments, the degenerative disease is osteoarthritis.

In some embodiments, the inflammatory condition is asthma, inflammatorybowel disease, or giant cell arteritis.

In some embodiments, the cardiovascular disease is an ischemic injury.

In some embodiments, the neurodegenerative disease is Alzheimer'sdisease, Down's syndrome, hereditary cerebral hemorrhage withamyloidosis-Dutch Type, cerebral amyloid angiopathy, Creutzfeldt-Jakobdisease, frontotemporal dementias, Huntington's disease, or Parkinson'sdisease.

In some embodiments, the infection is caused by leishmania,mycobacteria, including M. leprae, M. tuberculosis and/or M. avium,plasmodium, human immunodeficiency virus, Epstein Barr virus, Herpessimplex virus, or hepatitis C virus.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of inflammatory conditions, immunological conditions,autoimmune conditions, allergic conditions, rheumatic conditions,thrombotic conditions, cancer, infections, neurodegenerative diseases,degenerative diseases, neuroinflammatory diseases, cardiovasculardiseases, or metabolic conditions.

c. Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approvided for dosing per the FDA label insert.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot® and anticholinergics or antispasmodics such as dicyclomine(Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagylor ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected fromnucleoside reverse transcriptase inhibitors such as zidovudine(Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from chlorambucil (Leukeran®),cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine(Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from donepezil (Aricept®), rivastigmine (Excelon®),galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a compound of formula I andone or more additional therapeutic agents selected from a steroid,cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTKinhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, systemic lupus erythematosus (SLE), vasculitis,idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren'ssyndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, autoimmune gastritis, pernicious anemia, celiac disease,Goodpasture's syndrome, idiopathic thrombocytopenic purpura, opticneuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome,Takayasu's arteritis, temporal arteritis, warm autoimmune hemolyticanemia, Wegener's granulomatosis, psoriasis, alopecia universalis,Behcet's disease, chronic fatigue, dysautonomia, membranousglomerulonephropathy, endometriosis, interstitial cystitis, pemphigusvulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, ahyperproliferative disease, rejection of transplanted organs or tissues,Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1diabetes, graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, Crohn's disease, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin Anephropathy, interstitial lung disease, laryngitis, mastitis,meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cellproliferative disorder, e.g., diffuse large B cell lymphoma, follicularlymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia,acute lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, multiple myeloma (also known as plasma cellmyeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma,extranodal marginal zone B cell lymphoma, nodal marginal zone B celllymphoma, mantle cell lymphoma, mediastinal (thymic) large B celllymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis,breast cancer, prostate cancer, or cancer of the mast cells (e.g.,mastocytoma, mast cell leukemia, mast cell sarcoma, systemicmastocytosis), bone cancer, colorectal cancer, pancreatic cancer,diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting GCN2, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase, or a GCN2 protein kinase, or a mutantthereof, activity in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting GCN2, or a mutant thereof, activity in a patient comprisingthe step of administering to said patient a compound of the presentinvention, or a composition comprising said compound. In otherembodiments, the present invention provides a method for treating adisorder mediated by GCN2, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™.Letrozole is marketed under the trade names Femara™ or Femar™Aminoglutethimide is marketed under the trade name Orimeten™. Acombination of the invention comprising a chemotherapeutic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aPI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI1270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; othergeldanamycin related compounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or apharmaceutically acceptable salt thereof, especially the lactate salt.Somatostatin receptor antagonists as used herein refer to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (ParkeDavis), AWD-12-281 (AstaMedica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554/UM565(Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists;A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol(salbutamol), metaproterenol, terbutaline, salmeterol fenoterol,procaterol, and especially, formoterol and pharmaceutically acceptablesalts thereof. Suitable bronchodilatory drugs include anticholinergic orantimuscarinic compounds, in particular ipratropium bromide, oxitropiumbromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1 h68/GLV-h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8+ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+(Th17) and CD8+(Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetlL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Jerry L. Adams et al., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiments, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams et al. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams et al. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. Adamset al.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodimens, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodimens, a bispecificT cell engager (BiTE®) antibody construct is an EGFR/CD3 bispecificantibody construct. In some embodimens, a bispecific T cell engager(BiTE®) antibody construct activates T cells. In some embodimens, abispecific T cell engager (BiTE®) antibody construct activates T cells,which release cytokines inducing upregulation of intercellular adhesionmolecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, abispecific T cell engager (BiTE®) antibody construct activates T cellswhich result in induced bystander cell lysis. In some embodiments, thebystander cells are in solid tumors. In some embodiments, the bystandercells being lysed are in proximity to the BiTE®-activated T cells. Insome embodiment, the bystander cells comprises tumor-associated antigen(TAA) negative cancer cells. In some embodiment, the bystander cellscomprise EGFR-negative cancer cells. In some embodiments, animmuno-oncology agent is an antibody which blocks the PD-L1/PD1 axisand/or CTLA4. In some embodiments, an immuno-oncology agent is anex-vivo expanded tumor-infiltrating T cell. In some embodiments, animmuno-oncology agent is a bispecific antibody construct or chimericantigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8+(αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Preparation 1:3-(4-Methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

NBS (165.2 mg, 0.928 mmol) was added to a solution of2-[(E)-2-ethoxyvinyl]-4-methylsulfanyl-pyrimidine (181.4 mg, 0.924 mmol)in 1,4-dioxane (5.5 mL) and water (2 mL) and the reaction mixture wasstirred at ambient temperature for 15 min.5-(Trifluoromethyl)pyridin-2-amine (150 mg, 0.925 mmol) was added andthe reaction mixture heated at 65-75° C. for 7 hours. The mixture wascooled to ambient temperature and diluted with saturated aqueous NaHCO₃and extracted with DCM. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (silica, EtOAc/petrol gradient) to give3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (165mg, 58%); ESV-MS m/z 311.1 (M+H).

The following compounds were prepared using a methodology similar to theone described in Preparation 1:

-   6-Chloro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine    using 5-chloropyridin-2-amine;-   6-Chloro-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine    using 5-chloro-4-fluoro-pyridin-2-amine;-   6-Bromo-7-fluoro-3-(4-methyl    sulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine using    5-bromo-4-fluoro-pyridin-2-amine;-   6-Chloro-7-fluoro-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyridine    using 5-chloro-4-fluoropyridin-2-amine.

Preparation 2:3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

Sulfuryl chloride (174.9 μL, 2.160 mmol) was added to a solution of3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(165 mg, 0.532 mmol) and conc. HCl (47.1 μL of 37% w/w, 0.860 mmol) inMeCN (13 mL) and the reaction mixture stirred for 5 minutes. Cooledsaturated aqueous NaHCO₃ was added dropwise and the mixture stirred for10 min. The resultant precipitate was isolated by filtration, washedwith water and dried to give3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(125 mg, 79%).

The following compounds were prepared using a methodology similar to theone described in Preparation 2:

-   6-Chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine using    6-chloro-3-(4-methyl sulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine;-   6-Chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine    using 6-chloro-7-fluoro-3-(4-methyl    sulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine;-   6-Bromo-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine    using    6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine;-   6-Chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine    using    6-chloro-7-fluoro-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyridine.-   4-Chloro-2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}pyrimidine-   4-Chloro-2-{6-methanesulfonylimidazo[1,2-a]pyridin-3-yl}pyrimidine-   3-(4-Chloropyrimidin-2-yl)-N-cyclopropylimidazo[1,2-a]pyridine-6-sulfonamide-   3-(4-Chloropyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide

Preparation 3: 3-Bromo-6-(difluoromethyl)imidazo[1,2-a]pyridine

(Diethylamino)sulfur trifluoride (528.5 μL, 4.00 mmol) was addeddropwise to 3-bromoimidazo[1,2-a]pyridine-6-carbaldehyde (450 mg, 2.00mmol) in DCM (4.5 mL) at 0° C. After 2.5 hours, additional(diethylamino)sulfur trifluoride (150 μL, 1.135 mmol) was added and thereaction stirred at room temperature for 16 hours. The crude mixture wasdiluted with methanol and purified by means of an ion exchange SCX-2cartridge to afford 3-bromo-6-(difluoromethyl)imidazo[1,2-a]pyridine(310 mg, 63%); ESV-MS m/z 247.0 (M+H).

Preparation 4:2-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-ol

Step 1:6-(Difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2-a]pyridine

3-Bromo-6-(difluoromethyl)imidazo[1,2-a]pyridine (120 mg, 0.486 mmol),tributyl-(4-methoxypyrimidin-2-yl)stannane (200 μL, 0.583 mmol) andPdCl₂(PPh₃)₂(102.3 mg, 0.146 mmol) were combined in DMF (4 mL) anddegassed with nitrogen and heated at 120° C. for 16 hours. The mixturewas allowed to cool, filtered and then purified by reverse phasechromatography (C18; MeCN/water/0.05% TFA as eluent) to afford thetrifluoroacetic acid salt of6-(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2-a]pyridine (97mg, 72%); ESV-MS m/z 277.1 (M+H).

Step 2: 2-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-ol

Chlorotrimethylsilane (267 μL, 2.107 mmol) was added to a solution of6-(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2-a]pyridine (97mg, 0.351 mmol) and NaI (315.8 mg, 2.107 mmol) in MeCN (4 mL) and themixture was heated at 80° C. for 16 hours. The reaction mixture wascooled to room temperature and the solvent removed under reducedpressure. The residue was suspended in water and washed with saturatedaqueous sodium thiosulfate. The solid was filtered, washed with water,and dried under vacuum to afford2-[6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-ol (75 mg,81%); ESV-MS m/z 263.1 (M+H). The material was used without furtherpurification.

Preparation 5:3-(2-Chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

NBS (241 mg, 1.354 mmol) was added to a solution of2-chloro-4-(2-ethoxyvinyl)pyrimidine (250 mg, 1.354 mmol) in 1,4-dioxane(8 mL)/water (3 mL) and the reaction mixture was stirred for 15 min.5-(Trifluoromethyl)pyridin-2-amine (220 mg, 1.357 mmol) was added andthe reaction mixture heated at 80° C. for 3 hours. The mixture wascooled to room temperature and diluted with saturated aqueous NaHCO₃ andextracted with DCM. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (silica, EtOAc/petrol gradient, then MeOH/DCMgradient) to afford3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(234.5 mg, 58%) as a beige solid; ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (s,1H), 8.95 (s, 1H), 8.78 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.84 (dd,1H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −60.86; ESV-MS m/z 299.1 (M+H).

Preparation 6: N-[[(2S)-Morpholin-2-yl]methyl]methanesulfonamide

Step 1: tert-butyl(S)-2-(methylsulfonamidomethyl)morpholine-4-carboxylate

To a round bottom flask was added tert-butyl(2R)-2-(aminomethyl)morpholine-4-carboxylate (5 g, 23 mmol) and Et₃N(16.1 mL, 115 mmol) followed by THF (100 mL). DCM (50 mL) was added andthe mixture was cooled to 0° C. Methanesulfonyl chloride (2.4 mL, 30.5mmol) was added dropwise and the mixture stirred for 0.5 hours then leftat ambient temperature for 16 hours under an atmosphere of N₂. Thereaction was quenched with saturated aqueous NaHCO₃ solution (100 mL)and the majority of the volatiles were removed in vacuo. The aqueouslayer was extracted with ethyl acetate (3×50 mL). The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography (silica; 70-100% EtOAc/Petroleum ethergradient elution). The product fractions were combined and concentratedin vacuo. The residue was dried overnight under vacuum to givetert-butyl (S)-2-(methylsulfonamidomethyl)morpholine-4-carboxylate (3.61g, 53%) as a white solid; ¹H NMR (500 MHz, Chloroform-d) δ 4.71-4.59 (m,1H), 3.98-3.82 (m, 2H), 3.63-3.49 (m, 2H), 3.38-3.24 (m, 1H), 3.20-3.11(m, 1H), 3.04-2.90 (m, 4H), 2.73 (s, 1H), 1.49 (s, 9H).

Step 2: N-[[(2S)-Morpholin-2-yl]methyl]methanesulfonamide

TFA (9 mL, 115 mmol) was added to a stirred solution of tert-butyl(2S)-2-(methanesulfonamidomethyl)morpholine-4-carboxylate (3.6 g, 12mmol) in DCM (60 mL) and the reaction stirred at ambient temperature for6 hours. The solvent was removed in vacuo and the residue azeotropedwith DCM (×2) and diethyl ether (×2). The residue was taken up inmethanol and passed through an ion-exchange cartridge, eluting withmethanol (discarded) then a 2M methanolic ammonia solution. The filtratewas concentrated in vacuo to giveN-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (2.3 g, 97%); ¹H NMR(500 MHz, Chloroform-d) δ 4.73 (s, 1H), 3.90-3.87 (m, 1H), 3.65-3.60 (m,2H), 3.26 (dd, 1H), 3.09 (dd, 1H), 2.99 (s, 3H), 2.92-2.84 (m, 3H), 2.66(dd, 1H); MS m/z: 195 (M+H)⁺.

Preparation 7: 2-(1H-Pyrazol-4-yl)morpholine

Step 1: tert-Butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate

A mixture of tert-butyl 2-(2-oxoethyl)morpholine-4-carboxylate (5.77 g,25 mmol) and DMF-DMA (6.7 mL, 50 mmol) in DMF (50 mL) was stirred at 80°C. for 17 hours. The reaction mixture was cooled to ambient temperatureand the solvent removed in vacuo. The residue was taken up in EtOH (100mL) and hydrazine hydrate (1.3 mL, 26.5 mmol) was added with stirring atambient temperature. After 3 hours, the solvent was removed in vacuo andthe residue purified by chromatography (silica, PE/EtOAc gradientelution), to give tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate(2.35 g, 37%) as a yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 7.63(s, 2H), 4.52 (dd, 1H), 4.12 (br s, 1H), 3.97-3.90 (m, 2H), 3.68 (td,1H), 3.05 (d, 2H), 1.51 (s, 9H); MS m/z: 254.1 (M+H)⁺.

Step 2: 2-(1H-Pyrazol-4-yl)morpholine

3M HCl in methanol (45 mL of 3M, 135 mmol) was added to a stirredsolution of tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35g, 9.3 mmol) in DCM (75 mL) and the reaction heated at reflux for 5hours. The reaction was cooled to ambient temperature and the solventremoved in vacuo. The residue was dissolved in the minimum amount ofDCM/MeOH and loaded on to an ion-exchange cartridge. The cartridge waswashed with MeOH/DCM mixtures, which were discarded. The product waseluted by washing with 2M NH₃ in MeOH/DCM. The solvent was removed invacuo to give 2-(1H-pyrazol-4-yl)morpholine (1.27 g, 89%) as an orangesolid, which was taken on to the next reaction without furtherpurification; ¹H NMR (500 MHz, chloroform-d) δ 7.60 (s, 2H), 4.56 (dd,1H), 3.98 (ddd, 1H), 3.77 (td, 1H), 3.11 (dd, 1H), 3.00 (td, 1H),2x.93-2.88 (m, 2H); MS m/z: 154.2 [M+H]⁺.

Preparation 8: 2-Methyl-6-(1H-pyrazol-4-yl)morpholine

To a solution of 1-benzylpyrazole-4-carbaldehyde (2 g, 10.7 mmol) andnitromethane (7 mL, 129 mmol) cooled in an ice bath, was added Et₃N (150μL, 1.1 mmol). The mixture was stirred with cooling for 15 minutes, thenat ambient temperature for 18 hours. The reaction mixture wasconcentrated in vacuo and the residue purified by chromatography(silica, EtOAc/Petroleum ether gradient elution). The relevant fractionswere combined and concentrated in vacuo to give a colourless oil (1 g,37%); MS m/z: 248 (M+H)⁺. This material was taken directly onto the nextreaction.

A mixture of 1-(1-benzylpyrazol-4-yl)-2-nitro-ethanol (100 mg, 0.4mmol), Pd on C, wet, Degussa (20 mg, 0.2 mmol) in methanol (4 mL) wasstirred at ambient temperature for 18 hours under H₂ at 1 atmosphere.The reaction mixture was filtered and the filtrate concentrated in vacuoto give a colourless gum (90 mg); MS m/z: 218 (M+H)⁺. This material wastaken directly onto next the reaction.

2-Bromopropanoyl bromide (114 mg, 0.5 mmol) was added to an ice-coldsolution of 2-amino-1-(1-benzylpyrazol-4-yl)ethanol (100 mg, 0.5 mmol)and Et₃N (83 μL, 0.6 mmol) in DCM (4 mL) under N₂. The reaction mixturewas stirred at ambient temperature for 1 hour. The reaction mixture wasdiluted with DCM, washed with a 2M aqueous HCl solution, saturatedaqueous NaHCO₃ solution and brine. The organic phase was dried oversodium sulfate, filtered and concentrated in vacuo to give a colourlessoil. This material was taken up in THF (3 mL) and the solution cooled inan ice bath. Sodium hydride (37 mg of a 60% dispersion in mineral oil,0.9 mmol) was added and the resulting suspension was stirred at ambienttemperature for 2 hours. The reaction was quenched with methanol thendiluted with EtOAc, washed with a saturated aqueous sodium bicarbonatesolution and brine. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a pale yellow gum (100 mg), MS m/z: 272(M+H)⁺, that was taken directly on to next reaction withoutpurification.

A mixture of 6-(1-benzylpyrazol-4-yl)-2-methyl-morpholin-3-one (100 mg,0.4 mmol) and LiAlH₄ (184 μL of 2M, 0.4 mmol) in THF (3 mL) was stirredat 60° C. for 1 hour. The resulting suspension was quenched withNa₂SO₄.10H₂O pellets and stirred for 30 minutes, then filtered. Thefiltrate was concentrated in vacuo and the residue taken up in methanol(2 mL). Three drops of concentrated HCl and Pd on C, wet, Degussa (20mg, 0.02 mmol) were added to the solution. The reaction mixture wasstirred at ambient temperature under H₂ at 1 atmosphere pressure for 18hours. The reaction mixture was poured onto an ion-exchange cartridgeand eluted with methanol (filtrate discarded), then a 2M methanolic NH₃solution. The filtrate was concentrated in vacuo to give2-methyl-6-(1H-pyrazol-4-yl)morpholine (23 mg), MS m/z: 168 (M+H)⁺. Thismaterial was taken directly onto the next reaction.

Preparation 9: Imino(methyl)(piperidin-3-ylmethyl)-λ⁶-sulfanone

A mixture of tert-butyl 3-(chloromethyl)piperidine-1-carboxylate (500mg, 2.14 mmol), NaSMe (3 mL of 20% w/v, 8.56 mmol), KI (355 mg, 2.14mmol) in ethanol (10 mL) was stirred at 80° C. for 22 hours. Thereaction mixture was cooled to ambient temperature then concentrated invacuo. The residue was partitioned between EtOAc and saturated aqueoussodium bicarbonate solution. The organic phase was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo to give the product asa pale brown oil (460 mg 88%), that was taken on to the next stepwithout further purification or characterisation.

m-CPBA (324 mg, 1.88 mmol) was added to an ice cold solution oftert-butyl 3-(methylsulfanylmethyl)piperidine-1-carboxylate (460 mg,1.88 mmol) in DCM (7 mL) under N₂. The reaction mixture was stirred for20 hours, with the temperature rising to ambient. The reaction mixturewas diluted with DCM, washed with saturated aqueous sodium bicarbonatesolution and brine. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a pale brown oil (460 mg); MS m/z: 262(M+H)⁺, that was used in the next step without further purification orcharacterisation. tert-Butyl 3-(methylsulfinylmethyl)piperidine-1-carboxylate (5.5 g, 21.0 mmol),2,2,2-trifluoroacetamide (5.2 g, 46.3 mmol), diacetoxyiodobenzene (10.2g, 31.6 mmol) and MgO (3.39 g, 84.2 mmol) were combined in DCM (250 mL)under N₂. Rh₂(OAc)₆ (0.9 g, 2.0 mmol) was added and the reaction mixturemixture stirred at room temperature for 16 hours. The mixture wasfiltered through Celite, washing with methanol and DCM. The filtrate wasconcentrated in vacuo and the residue taken up in methanol (5 mL) andMeCN/water (3:1) (5 mL). K₂CO₃ (17.4 g, 126.0 mmol) was added and themixture stirred at 90° C. for 2 hours. The mixture was diluted withEtOAc and washed with saturated aqueous sodium bicarbonate solution andbrine. The organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo to give tert-butyl3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (5.96 g,quantitative yield) as an amber oil; MS m/z: 277 (M+H)⁺, that was takendirectly on to the next reaction.

tert-Butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600mg, 2.17 mmol) in DCM (3 mL) was treated with TFA (1.7 mL, 21.7 mmol).The mixture was stirred at room temperature for 16 hours. The reactionmixture was concentrated in vacuo. The residue was taken up in methanoland loaded on to an ion-exchange cartridge. The cartridge was elutedMeOH/DCM (filtrate discarded) then with methanolic ammonia. The filtratewas concentrated in vacuo to giveimino(methyl)(piperidin-3-ylmethyl)-λ⁶-sulfanone (250 mg, 65%); ¹H NMR(500 MHz, Methanol-d₄) δ 3.34-3.24 (m, 1H), 3.19-3.10 (m, 2H), 3.10-3.07(m, 3H), 3.05-2.97 (m, 1H), 2.60 (ddd, 1H), 2.52-2.43 (m, 1H), 2.30-2.18(m, 1H), 2.08 (ddtd, 1H), 1.75 (dq, 1H), 1.61 (dtq, 1H), 1.37 (dtd, 1H).

Preparation 10: Imino(methyl)(piperidin-3-ylmethyl)-λ⁶-sulfanone

Sodium thiomethoxide (4.06 g, 58 mmol) was added to a solution oftert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (8.5 g,29 mmol) in ethanol (170 mL). The mixture was stirred at ambienttemperature for 6 hours then concentrated in vacuo. The residue waspartitioned between DCM and saturated aqueous NaHCO₃ solution. Theorganic phase was dried and concentrated in vacuo. The residue waspurified by chromatography (silica, MeOH/DCM gradient elution) to give apale yellow oil (6.9 g). This material was dissolved in DCM (100 mL) andthe solution cooled in an ice bath. m-CPBA (6.93 g of 70% pure w/w, 28mmol) was added portionwise. After addition was complete the reactionmixture was stirred for 10 minutes then partitioned between DCM,saturated aqueous sodium bicarbonate solution and saturated aqueoussodium thiosulfate solution. The organic phase was dried andconcentrated in vacuo. The residue was purified by chromatography(silica, DCM/MeOH gradient elution) to give the product as a colourlessoil.

tert-Butyl 3-((methylsulfinyl)methyl)piperidine-1-carboxylate (5.5 g,21.0 mmol), 2,2,2-trifluoroacetamide (5.23 g, 46.3 mmol),(diacetoxyiodo)benzene (10.17 g, 31.6 mmol) and magnesium oxide (3.39 g,84.2 mmol) were dissolved in DCM (250 mL) anddiacetoxy(diacetoxyrhodio)rhodium (0.9 g, 2.04 mmol) was added. Themixture was stirred at ambient temperature overnight before beingfiltered through Celite and concentrated in vacuo. The residue wasdissolved in methanol (50 mL) and water (10 mL) and K₂CO₃ (17.44 g,126.2 mmol) was added. The mixture was stirred at ambient temperaturefor 3 hours before heating 50° C. for 3 days. The mixture wasconcentrated in vacuo and the residue dissolved in methanol (5 mL) andacetonitrile/water (3:1 mixture, 5 mL). After 1.5 hours at 90° C. themixture was cooled, diluted in EtOAc and washed with brine and saturatedaq. NaHCO₃ solution. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to give tert-butyl3-((S-methylsulfonimidoyl)methyl)piperidine-1-carboxylate (5.96 g) as anamber oil which was used without further purification.

A solution of tert-butyl3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600 mg, 2.17mmol) and TFA (1.67 mL, 21.71 mmol) in DCM (3 mL) was stirred at ambienttemperature for 16 hours before being concentrated in vacuo and theresidue passed through an SCX-2 cartridge. The product was eluted withammonia in methanol to giveimino(methyl)(piperidin-3-ylmethyl)-λ⁶-sulfanone (250 mg, 65%); ¹H NMR(500 MHz, Methanol-d₄) δ 3.34-3.24 (m, 1H), 3.19-3.10 (m, 2H), 3.10-3.07(m, 3H), 3.05-2.97 (m, 1H), 2.60 (ddd, J=12.4, 11.5, 3.1 Hz, 1H),2.52-2.43 (m, 1H), 2.30-2.18 (m, 1H), 2.08 (ddtd, J=30.1, 10.9, 3.8, 1.8Hz, 1H), 1.75 (dq, J=13.8, 3.3 Hz, 1H), 1.61 (dtq, J=13.6, 11.5, 3.8 Hz,1H), 1.37 (dtd, J=12.8, 11.3, 3.9 Hz, 1H).

Preparation 11: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

Step 1: 1-(tert-Butyl) 3-methyl 2,5-dimethylpiperidine-1,3-dicarboxylate

A mixture of methyl 2,5-dimethylpyridine-3-carboxylate (2.6 g, 15.74mmol) and PtO₂ (713 mg, 3.14 mmol) in HCl (57 mL of a 3M solution inMeOH, 171.1 mmol) was stirred under a balloon of H₂. The reactionmixture was stirred for 16 hours at ambient temperature before beingfiltered through Celite and the filtrate concentrated in vacuo. Theresidue was dissolved in THF (27 mL) and triethylamine (6.6 mL, 47.3mmol), DMAP (96 mg, 0.79 mmol) and di-tert-butyl dicarbonate (17.4 mL ofa 1M solution in THF, 17.4 mmol) sequentially added. The reactionmixture was stirred for 16 hours, then partitioned between EtOAc andwater. The organic layer was separated and washed with NH₄Cl solution,water (1×), brine (1×), then dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by chromatography (silica, 0-10%EtOAc/Petroleum ether gradient elution) to give 1-(tert-butyl) 3-methyl2,5-dimethylpiperidine-1,3-dicarboxylate (1.4 g, 33%) as a colourlessoil containing a mixture of diastereomers; ¹H NMR (400 MHz, Methanol-d₄)δ 4.80-4.62 (m, 1H), 3.95-3.78 (m, 1H), 3.71 (d, 3H), 2.71 (dq, 1H),2.46 (dt, 1H), 1.89-1.77 (m, 1H), 1.48 (q, 10H), 1.10-0.92 (m, 7H).

Step 2: tert-Butyl3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate

O1-tert-Butyl 03-methyl 2,5-dimethylpiperidine-1,3-dicarboxylate (1.40g, 5.16 mmol) was dissolved in THF (42 mL) and cooled to 0° C. Lithiumborohydride (10.3 mL of a 2M solution in THF, 20.6 mmol) was added andthe reaction allowed to warm to ambient temperature. After 30 minutesthe reaction mixture was warmed to 50° C. and stirred for 16 hours. Thereaction was cooled to ambient temperature then quenched with water. Themixture was extracted with EtOAc (×3). The combined organics were driedand concentrated in vacuo to give tert-butyl3-(hydroxymethyl)-2,5-dimethyl-piperidine-1-carboxylate (1.25 g, 100%)as a colourless oil that was taken directly on to the next reactionwithout further purification; ¹H NMR (400 MHz, Methanol-d₄) δ 4.42-4.27(m, 1H), 3.82-3.68 (m, 1H), 3.34-3.23 (m, 2H), 2.33 (dt, 1H), 1.91 (s,1H), 1.82-1.68 (m, 1H), 1.54-1.37 (m, 2H), 1.35 (s, 9H), 0.95-0.87 (m,3H), 0.86-0.76 (m, 4H).

Step 3: tert-Butyl2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Methanesulfonyl chloride (2.77 mL, 35.7 mmol) was added to a solution oftert-butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate (5.80g, 23.8 mmol) and triethylamine (6.64 mL, 47.7 mmol) in DCM (116 mL)stirring at 0° C. After 30 mins the reaction was quenched with saturatedaq. NaHCO₃, stirred for 5 mins and then the layers separated using aphase separator cartridge. The organic phase was evaporated in vacuo togive tert-butyl2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate(7.6 g) which was used directly in the next step without furtherpurification.

Step 4: tert-Butyl2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate

Sodium thiomethoxide (9.94 g, 141.8 mmol) was added to a solution oftert-butyl2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate(7.6 g, 23.6 mmol) in EtOH (100 mL), stirring at 0° C. After addition,cooling was removed and the reaction heated at 60° C. for 16 hours. Thereaction was cooled to ambient temperature, concentrated in vacuo andpurified by column chromatography (silica, eluting with 0-12.5% MeOH inDCM gradient) to give tert-butyl2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate (3.4 g, 66%)as a colourless oil; ¹H NMR (500 MHz, Methanol-d₄) δ 4.53-4.43 (m, 1H),3.86 (td, J=13.3, 4.4 Hz, 1H), 2.53-2.31 (m, 3H), 2.10 (s, 3H),1.91-1.81 (m, 1H), 1.74-1.63 (m, 1H), 1.61-1.50 (m, 1H), 1.48 (s, 9H),1.10-0.99 (m, 4H), 0.93 (t, J=6.4 Hz, 3H).

Step 5: tert-Butyl2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate

tert-Butyl 2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate(2 g, 7.31 mmol) was dissolved in DCM (73 mL) and the solution cooled to0° C. m-CPBA (1.80 g, 7.31 mmol) was added portionwise over 5 min andthe reaction stirred for a further 5 min before being quenched byaddition of saturated aqueous sodium thiosulphate (40 mL) and stirredfor 5 min before extracting with DCM (3×50 mL). The combined organicswere washed with with saturated aq. NaHCO₃ (2×40 mL), filtered through aphase separator cartridge and concentrated in vacuo to give tert-butyl2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate (2.1 g,100%) as a colourless oil which was used without further purification.

Step 6: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

tert-Butyl2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate (2.1 g,7.26 mmol) was dissolved in methanol (36 mL) and 4M HCl in dioxane (9.1mL, 36.3 mmol) was added. The reaction was stirred for 16 hours atambient temperature before being concentrated in vacuo to give2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine (1.85 g, 97%) as awhite solid; MS m/z: 190.1 (M+H)⁺.

Preparation 12: 2-(1H-Pyrazol-4-yl)piperazine

A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol), PtO2 (100mg, 0.4 mmol) in methanol (15 mL) was shaken at ambient temperatureunder a 60 psi H₂ pressure for 18 hours. The reaction mixture wasfiltered and the filtrate concentrated in vacuo to give2-(1H-pyrazol-4-yl)piperazine as a colourless oil, which was takendirectly on to the next reaction without purification; MS m/z: 153(M+H)⁺.

Preparation 13: 2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazine

A 3-necked flask equipped with reflux condenser and thermometer wascharged with 3-chloro-2,5-dimethyl-pyrazine (5 mL, 40 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate(10 g, 34 mmol) in 1,4-dioxane (100 mL). Pd(PPh₃)₄(2 g, 2 mmol), andNa₂CO₃ (60 mL of 2M, 100 mmol) were added and the solution was evacuatedand backfilled with N₂ (×2). The solution was heated at 100° C. andstirred overnight. The reaction mixture was cooled to ambienttemperature and filtered, washing with diethyl ether. The filtrate wasconcentrated in vacuo and the residue purified by chromatography(silica, 0-100% [EtOAc+2% 2M methanolic ammonia]-Petroleum ethergradient elution). The product fractions were combined and concentratedin vacuo to give 2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazine as a whitesolid (4.5 g, 64%); MS m/z: 175 (M+H)⁺.

A mixture of 2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazine (4.5 g, 26 mmol),PtO₂ (1 g, 4 mmol) and HCl (60 mL of a 3M solution in MeOH, 200 mmol)was shaken in a Parr hydrogenator for 24 hours under a pressure of 60psi H₂. The reaction mixture was filtered and the filtrate concentratedin vacuo to give the product 2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazineas an off-white solid (4.0 g, 61%); MS m/z: 181 (M+H)⁺. This materialwas used in the next reaction assuming the dihydrochloride salt wasisolated.

The following compounds were prepared using a methodology similar to theone described in Preparation 213:

-   2-Methyl-6-(1H-pyrazol-4-yl)piperazine;-   3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazine.

Preparation 14: Dimethyl((5-methylpiperidin-3-yl)imino)-λ⁶-sulfanone

Step 1: Dimethyl((5-methyl-pyridin-3-yl)imino)-λ⁶-sulfanone

3-Bromo-5-methyl-pyridine (250 g, 1.439 mol), iminodimethyl-λ⁶-sulfane(142.6 g, 1.454 mol), Xantphos (24.976 g, 43.16 mmol), K₂CO₃ (218.8 g,1.583 mol) and tris(benzylideneacetone)dipalladium(0) (19.76 g, 21.58mmol) were suspended in 1,4-dioxane (2.4 L). The reaction mixture wasdegassed (vacuum/nitrogen 3 cycles) and stirred under reflux at 125° C.for 16 hours. The reaction mixture was allowed to cool to ambienttemperature then filtered through Celite washing with EtOAc. The oil wasdiluted with a little MTBE (just enough to see hint of precipitation;−150 ml), seeded with a few crystals of an authentic sample and stirredat ambient temperature for 2 hours. The solid was filtered and washedwith a minimum of MTBE to give a light pink solid which was dried in theoven at 30° C. in vacuo to give the desired product (105.9 g, 40%). Themother liquors were concentrated in vacuo to give 247.4 g of a darkbrown oil. 247.4 g of crude mixture was purified on column columnchromatography (3 kg silica column; product adsorbed onto 350 g silicapad; 0 to 10% MeOH in EtOAc). Product-containing fractions were combinedand concentrated in vacuo to give the product after trituration withdiethyl ether (106.4 g 40%). Total yield 212.3 g (80%); ¹H NMR (400 MHz,DMSO-d₆) δ 7.97 (d, J 2.4 Hz, 1H), 7.92 (dd, J 1.9, 0.9 Hz, 1H), 7.13(dq, J 2.8, 0.9 Hz, 1H), 3.25 (s, 6H), 2.22 (d, J 0.8 Hz, 3H); ESV-MSm/z 185.0 (M+1)⁺.

Step 2:1-Benzyl-3-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)-5-methylpyridin-1-iumbromide

To a solution of dimethyl((5-methyl-pyridin-3-yl)imino)-λ⁶-sulfanone(105.9 g, 574.73 mmol) in MeCN (900 mL) was added BnBr (69 mL, 580mmol). The mixture was stirred at 100° C. for 4 hours. The reactionmixture was allowed to cool to ambient temperature and the resultingprecipitate collected by filtration, washing with cold MeCN. The productwas obtained as an off-white solid (158.8 g, 78%); ¹H NMR (400 MHz,DMSO-d₆) δ 8.55 (s, 1H), 8.48 (t, J 1.8 Hz, 1H), 7.87 (t, J=1.5 Hz, 1H),7.58-7.49 (m, 2H), 7.49-7.37 (m, 3H), 5.67 (s, 2H), 3.44 (s, 6H), 2.41(s, 3H). ESV-MS m/z 275.1 (M+1)⁺.

Step 3: ((1-benzyl-,5-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ⁶-sulfanone

A solution of NaBH₄ (43 g, 1.137 mol) in sodium hydroxide (1.6 L of 0.01M 16.00 mmol) was added dropwise via syringe pump over 2 hours to asolution of1-benzyl-3-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)-5-methylpyridin-1-iumbromide (200 g, 562.9 mmol) in ethanol (600 mL)/water (600 mL) at 0° C.under N₂. The mixture was extracted with MTBE (3×1.6 L), the organicscombined and washed with brine (1×600 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give the desired product (142 g, 91%); 1H NMR(400 MHz, Chloroform-d) δ 7.40-7.17 (m, 5H), 5.18-5.10 (m, 1H), 3.58 (s,2H), 3.08 (d, J=1.9 Hz, 6H), 3.04-2.93 (m, 1H), 2.86-2.68 (m, 3H),2.55-2.40 (m, 1H), 1.92 (dd, J=11.0, 8.2 Hz, 1H), 0.95 (d, J=6.9 Hz,3H). ESV-MS m/z 279.1 (M+1)⁺.

Step 4: Dimethyl((5-methylpiperidin-3-yl)imino)-λ⁶-sulfanone

Pd(OH)₂, (59 g, 20% w/w, Degussa, 84.03 mmol) was transferred to anitrogen-filled bottle and the vessel evacuated and re-filled withnitrogen. A solution of((1-benzyl-,5-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ⁶-sulfanone(117 g, 420.2 mmol) in methanol (700 mL) was then added and theresulting solution degassed by vacuum/nitrogen cycles (×3). Theatmosphere was exchanged by vacuum/hydrogen cycles and the reactionmixture was shaken on a Parr hydrogenator for 16 hours. The reactionmixture was cooled to ambient temperature then was filtered throughCelite and concentrated in vacuo to leave an orange oil which wasanalysed and showed incomplete reaction. The product was redissolved inmethanol (700 mL) and added to the Parr bottle containingdihydroxypalladium (59 g of 20% w/w, 84.03 mmol). The mixture was thenshaken at 50° C. and 30 psi of molecular hydrogen overnight. Thereaction mixture was cooled to ambient temperature then filtered throughCelite and the filtrate concentrated in vacuo to leave an orange oilwhich was analysed by UPLC-MS—showing incomplete reaction. The mixturewas again redissolved in methanol (700 mL) and added to a Parr bottlecontaining dihydroxypalladium (59 g of 20% w/w, 84.03 mmol). The mixturewas shaken at 50° C. and under a 30 psi atmosphere of molecular hydrogenon a Parr hydrogenator overnight. The mixture was cooled to ambienttemperature then filtered through Celite before concentrating in vacuoto give dimethyl((5-methylpiperidin-3-yl)imino)-λ⁶-sulfanone (56.7 g,71%); 1H NMR (500 MHz, DMSO-d₆) δ 3.54 (masked signal, 1H), 3.09 (tt,J=10.8, 4.4 Hz, 1H), 2.95 (s, 6H), 2.89-2.74 (m, 2H), 2.11 (dd, J=12.0,10.3 Hz, 1H), 1.92 (dd, J=12.1, 11.0 Hz, 1H), 1.84-1.73 (m, 1H),1.58-1.44 (m, 1H), 0.89 (d, J=12.4 Hz, 1H), 0.77 (d, J=6.6 Hz, 3H).

The following compound was prepared using a methodology similar to theone described in Preparation 214:

Dimethyl((piperidin-3-yl)imino)-λ⁶-sulfanone Preparation 15:2,5-Dimethylpiperidine-3-carboxamide

Step 1: 2,5-Dimethylnicotinamide

Methyl 2,5-dimethylpyridine-3-carboxylate (100 mg, 0.61 mmol) wasdissolved in ammonium hydroxide (480 μL, 12.3 mmol) and the mixtureheated to 70° C. in a sealed tube. After 16 hours the reaction wasdiluted in water and the mixture concentrated in vacuo to give2,5-dimethylpyridine-3-carboxamide (91 mg, 100%) as a white solid; MSm/z: 151.0 (M+H)⁺.

Step 2: 2,5-Dimethylpiperidine-3-carboxamide

2,5-dimethylnicotinamide (99 mg, 0.66 mmol) and PtO₂ (30.4 mg, 0.13mmol) were dissolved in methanol (3 mL) and 3M HCl (1.1 mL, 3.30 mmol).The mixture was degassed and stirred under a balloon of H₂ for 90 minbefore being passed through Celite and the filtrate concentrated invacuo to give 2,5-dimethylpiperidine-3-carboxamide (dihydrochloridesalt) (150 mg, 99%); MS m/z: 157.0 (M+H)⁺.

Preparation 16:N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

Step 1: Benzyl3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate

Benzyl 3-methyl-4-oxo-piperidine-1-carboxylate (20 g, 0.08 mol) wasdissolved in THF (300 mL) under N₂. The solution was cooled to −78° C.and LiHMDS (1M in THF, 101.1 mL, 0.1 mol) was added dropwise over 20minutes, keeping the temperature below −70° C. After stirring at −78° C.for 90 minutes, a solution of 2-(chloromethyl)isoindoline-1,3-dione(23.7 g, 0.12 mol) in THF (200 mL) was added dropwise over 25 minutes,keeping the temperature below −70° C. The reaction was stirred at −78°C. for 1 hour then quenched at −78° C. by the addition of saturatedaqueous ammonium chloride solution (65 mL) and the mixture allowed towarm to ambient temperature. The reaction was repeated and the twomixtures obtained were combined and extracted with EtOAc (300 mL). Theorganic phase was washed with saturated aqueous sodium bicarbonatesolution (300 mL) and brine (300 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography(silica, EtOAc/Petroleum ether elution). Product fractions were combinedand concentrated in vacuo and the residue recrystallized from EtOAc togive the product as a white solid (7.56 g, 23%).

Step 2: Benzyl(3R,5S)-3-[(1,3-Dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate

A flask was charged with benzyl3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate(60 g, 0.15 mol) and cooled in an ice/water bath. DAST (325 mL, 2.5 mol)was added in one portion and the mixture stirred at ambient temperaturefor 3 days. The resulting yellow solution was diluted with DCM (1 L) andslowly added to a mixture of ice/water and solid sodium bicarbonate withoverhead stirring. The temperature remained below 0° C. and additionalsodium bicarbonate was added to maintain a pH of 7-8. The mixture waswarmed to ambient temperature and the layers separated. The aqueousphase was extracted with DCM (2 L). The combined organics were washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by chromatography (silica, EtOAc/Petroleum etherelution). Product fractions were combined and concentrated in vacuo. Theproduct benzyl3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate,was obtained as a glass (32.5 g, 51%); ¹H NMR (400 MHz, chloroform-d) δ7.89-7.64 (4H, m), 7.42-7.11 (5H, m), 5.15-5.03 (2H, m), 4.39-4.07 (3H,m), 3.83-3.66 (1H, m), 2.97-2.60 (2H, m), 2.56-2.31 (1H, m), 2.08-1.89(1H, m), 1.05 (3H, d) as a mixture of isomers.

Preparative chiral supercritical fluid chromatography (conditions:Chiralpak® IC 5 μm, CO₂/iPrOH 90/10, 230 nm) was used to isolate thesingle enantiomer benzyl(3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate,(98.7% ee).

Step 3: Benzyl(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-piperidine-1-carboxylate

To a suspension of benzyl(3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate(9.6 g, 22.4 mmol) in ethanol (144 mL) was added hydrazine hydrate (8.5mL, 112 mmol). The reaction mixture was heated to reflux for 5 hoursthen allowed to cool to ambient temperature overnight. The resultingsuspension was filtered and the precipitate washed with EtOH (×2). Thefiltrate was loaded onto ion-exchange cartridges (50 g×10). Thecartridges were washed with MeOH/DCM mixtures (filtrates discarded),then with 2M methanolic ammonia solution. The filtrates were combinedand concentrated in vacuo. The residue was taken up in methanol andconcentrated in vacuo (×2), then treated with heptane and concentratedin vacuo. The resulting yellow oil was dried under vacuum overnight togive the product as a solid (6.77 g), which was taken directly on to thenext reaction; ¹H NMR (400 MHz, DMSO-d₆) δ 7.48-7.17 (m, 5H), 5.11 (s,2H), 4.41 (ddt, 1H), 4.02 (d, 1H), 2.98 (dd, 1H), 2.64 (s, 2H), 2.41(dd, 1H), 2.15-1.78 (m, 2H), 1.50 (s, 2H), 0.93 (d, 3H); MS m/z: 299(M+H)⁺.

Step 4: Benzyl(3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methyl-piperidine-1-carboxylate

Benzyl(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-piperidine-1-carboxylate(6.6 g, 22 mmol) was dissolved in DCM (66 mL) and cooled in an ice bath.The internal temperature reached was 3° C. Et₃N (3.4 mL, 24 mmol) wasadded with stirring. Methanesulfonyl chloride (1.88 mL, 24 mmol) wasadded over 5 minutes, at such a rate to keep the internal temperaturebelow 10° C. After 30 minutes, the ice bath was removed. The solutionwas warmed up to ambient temperature and quenched with a saturatedaqueous NaHCO₃ solution (66 mL). The layers were separated and theaqueous phase extracted with DCM (33 mL). The combined organics weredried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography (silica; 0 to 100% EtOAc/Petroleum ethergradient elution). The product fractions were combined and concentratedin vacuo. The residue was dried overnight under vacuum to give a whitesolid (7.92 g; 95%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.31 (m, 5H),7.31-7.19 (m, 1H), 5.12 (s, 2H), 4.37 (d, 1H), 4.18-3.94 (m, 1H), 3.38(ddd, 1H), 3.00-2.80 (m, 4H), 2.68 (s, 2H), 2.15 (s, 2H), 0.95 (d, 3H);MS m/z: 377 (M+H)⁺.

Step 5:N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

To a solution of benzyl(3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methyl-piperidine-1-carboxylate(7.54 g, 20 mmol) in DCM (113 mL) was added Et₃N (8.38 mL, 60 mmol),followed by Pd(OAc)₂ (1.799 g, 8 mmol). Et₃SiH (19.20 mL, 120 mmol) wasadded over 5 minutes. The solution was stirred at ambient temperaturefor 1 hour then separated into 6 equal portions and loaded ontoion-exchange cartridges (50 g). The cartridges were washed with DCM, 1:1MeOH:DCM and methanol. The filtrates were discarded. The cartridges werewashed with 2M methanolic ammonia solution. The filtrates were combinedand concentrated in vacuo. The residue was azeotroped with DCM thentaken up in methanol (45 mL) and stirred with SPM32 (3-mercaptopropylethyl sulfide silica) for 2 hours at ambient temperature, then at 50° C.for 1 hour. The mixture was cooled and filtered through Celite and thefiltrate concentrated in vacuo. The residue was taken up in DCM andconcentrated in vacuo. The residue was dried overnight under vacuum togiveN-(((3S,5S)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamideas a white solid (4.40 g, 91%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.10 (t,1H), 3.43-3.33 (m, 1H), 3.26-3.10 (m, 1H), 2.93-2.88 (m, 4H), 2.79 (dtd,1H), 2.38-2.20 (m, 2H), 2.13-1.78 (m, 2H), 0.89 (d, 3H); MS m/z: 243.0(M+H)⁺.

Preparation 17: N-(Pyrrolidin-3-ylmethyl)methanesulfonamide

Step 1: tert-Butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate

Methanesulfonyl chloride (222 mg, 150 μL, 1.938 mmol) was added to astirred solution of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate(300 mg, 1.498 mmol) and triethylamine (232.3 mg, 320 μL, 2.296 mmol) inTHF (10 mL) under an atmosphere of nitrogen and the reaction was stirredat ambient temperature for 1.5 hours. The reaction was diluted with DCMand saturated aqueous NaHCO₃ and the mixture was stirred for 10 minutes.The layers were separated and the aqueous layer extracted with DCM (×2).The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to give tert-butyl3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate as a pale yellowoil that was deprotected assuming 100% yield and purity; ¹H NMR (500MHz, DMSO-d₆) δ 7.11 (t, J=6.2 Hz, 1H), 3.40-3.35 (m, 1H), 3.32-3.28 (m,1H), 3.23-3.15 (m, 1H), 2.95-2.93 (m, 3H), 2.89 (s, 3H), 2.31-2.26 (m,1H), 1.93-1.88 (m, 1H), 1.65-1.52 (m, 1H), 1.40 (s, 9H); ESV-MS m/zcalc. 278.13004, found 223.1 (M+1)⁺.

Step 2: N-(Pyrrolidin-3-ylmethyl)methanesulfonamide

TFA (2.960 g, 2 mL, 25.96 mmol) was added to a stirred solution oftert-butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate (417mg, 1.498 mmol) in DCM (20 mL) and the reaction mixture was stirred atambient temperature for 15 hours. The solvent was removed in vacuo andthe residue azeotroped with DCM (×2) and diethyl ether (×2). The residuewas passed through a 10 g SCX-2 cartridge and washed with MeOH/DCMmixtures. The product was eluted by washing the cartridge with 2M NH₃ inMeOH/DCM mixtures. The solvent was removed in vacuo to giveN-(pyrrolidin-3-ylmethyl)methanesulfonamide (227.4 mg, 85%) as a paleyellow solid; ¹H NMR (500 MHz, chloroform-d) δ 3.16 (qd, J=12.3, 6.5 Hz,2H), 3.09-3.03 (m, 2H), 2.98 (s, 3H), 2.94-2.89 (m, 1H), 2.75 (dd,J=10.7, 5.0 Hz, 1H), 2.40-2.32 (m, 1H), 2.04-1.96 (m, 1H), 1.55-1.48 (m,1H). ESV-MS m/z 179.2 (M+1)⁺.

Preparation 18: 4-Pyrrolidin-3-yl-1H-pyrazole

Step 1: tert-Butyl 3-(1H-pyrazol-4-yl)-2,5-dihydropyrrole-1-carboxylate

tert-Butyl 4-bromopyrazole-1-carboxylate (230 mg, 0.931 mmol),tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate(250 mg, 0.847 mmol) and potassium carbonate (1.3 mL of 2M, 2.60 mmol)were combined in dioxane (3 mL) and the mixture de-gassed (×2 vacuumcycles). Pd(dppf)Cl₂.DCM (70 mg, 0.086 mmol) was added and the mixturede-gassed (×2 vacuum cycles) then heated at 90° C. overnight. Thereaction mixture was partitioned between EtOAc and water. The organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by chromatography (silica, 0-100% EtOAc/Petroleumether gradient elution). Product fractions were combined andconcentrated to give the product as a pale yellow film (65 mg, 33%) thatwas taken on to the next reaction. ESV-MS m/z 236.0 (M+1)⁺.

Steps 2 and 3: 4-Pyrrolidin-3-yl-1H-pyrazole

tert-Butyl 3-(1H-pyrazol-4-yl)-2,5-dihydropyrrole-1-carboxylate (550 mg,2.338 mmol) was dissolved in DCM (10 mL) and TFA added. After 1 hour thereaction mixture was concentrated in vacuo and the residue azeotropedwith DCM (×2). The residue was taken up in methanol (10 mL) and thesolution degassed (×3 vacuum—N₂ cycles). Pd on C, wet, Degussa (200 mgof 10% w/w, 0.188 mmol) was added and the mixture degassed (×3 cycles).The N₂ atmosphere was replaced with hydrogen (×3 cycles) and the mixturestirred at ambient temperature. After 90 minutes the reaction mixturewas filtered over Celite, washing with methanol. The filtrate wasconcentrated in vacuo (cold water bath) to give crude4-pyrrolidin-3-yl-1H-pyrazole (trifluoroacetate salt) (600 mg,quantitative yield); ESV-MS m/z 136.0 (M+1)⁺

Preparation 19: (E)-2-(2-Ethoxyvinyl)-4-(methylthio)pyrimidine

To a suspension of 2-chloro-4-(methylthio)pyrimidine (56.1 g, 349.3mmol) and 2 M aq. Na₂CO₃ (524 mL, 1.05 mol) in 1,2-dimethoxyethane (730mL) was added2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.1 g,384 mmol). Pd(PPh₃)₄(20.2 g, 17.5 mmol) was added and the mixturedegassed. The reaction was placed under a nitrogen atmosphere and heatedat reflux for 4 hours. The mixture was cooled to ambient temperature andpartitioned between EtOAc (1.1 L) and water (560 mL). The organic layerwas washed with water (2×560 mL), the combined organic layers werere-extracted with EtOAc (280 mL) and the combined organic phases werewashed with brine (×1), dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by column chromatography (silica,eluting with 0 to 25% EtOAc/petroleum ether) to give(E)-2-(2-ethoxyvinyl)-4-(methylthio)pyrimidine as a pale yellow,crystalline solid (62.4 g, 91%); ¹H NMR (500 MHz, Chloroform-d) δ 8.18(d, J=5.5 Hz, 1H), 7.95 (d, J=12.6 Hz, 1H), 6.85 (d, J=5.5 Hz, 1H), 5.91(d, J=12.6 Hz, 1H), 4.02 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.40 (t, J=7.0Hz, 3H); ES+[M+H]=197.1.

Preparation 20:2-chloro-4-{6-cyclopropylimidazo[1,2-a]pyridin-3-yl}pyrimidine

Step 1: 6-Cyclopropylimidazo[1,2-a]pyridine. Into a 150-mL round-bottomflask, was placed 6-bromoimidazo[1,2-a]pyridine (5 g, 22.84 mmol, 1equiv, 90%), cyclopropylboronic acid (3.1 g, 34.26 mmol, 1.50 equiv,95%), Pd(dppf)Cl₂.CH₂Cl₂ (2.0 g, 2.33 mmol, 0.10 equiv, 95%), dioxane(20 mL, 224.28 mmol, 9.82 equiv, 95%), K₃PO₄ (10.2 g, 45.68 mmol, 2.00equiv, 95%). The resulting solution was stirred for overnight at 100degrees C. in an oil bath. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/5). This resulted in 3.6 g (89.67%) of6-cyclopropylimidazo[1,2-a]pyridine as a white solid.

Step 2: 3-Bromo-6-cyclopropylimidazo[1,2-a]pyridine. Into a 150-mLround-bottom flask, was placed 6-cyclopropylimidazo[1,2-a]pyridine (3.6g, 20.48 mmol, 1 equiv, 90%), NBS (3.8 g, 20.28 mmol, 0.99 equiv, 95%),DCM (20 mL, 298.87 mmol, 14.59 equiv, 95%). The resulting solution wasstirred for 3 hr at 25 degrees C. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/5). This resulted in 4.3 g (79.70%) of3-bromo-6-cyclopropylimidazo[1,2-a]pyridine as a white solid.

Step 3: 2-Chloro-4-{6-cyclopropylimidazo[1,2-a]pyridin-3-yl}pyrimidine.To a stirred solution of 3-bromo-6-cyclopropylimidazo[1,2-a]pyridine(1.5 g, 5.694 mmol, 1 equiv, 90%) in THF (10 mL, 117.259 mmol, 21.0equiv, 95%) was added iPrMgCl.LiCl (1.74 g, 11.388 mmol, 2 equiv, 95%)dropwise at −10 degrees Celsius under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 0 degrees Celsius under nitrogenatmosphere. The above mixture was added into a stirred mixture of2,4-dichloropyrimidine (1.07 g, 6.824 mmol, 1.20 equiv, 95%) andPd(PPh₃)₄(0.35 g, 0.285 mmol, 0.05 equiv, 95%) in THF (10 mL, 117.259mmol, 21.0 equiv, 95%) at room temperature. The resulting mixture wasstirred for additional 4 h at 70 degrees Celsius. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/10). This resulted in 1 g (58.39%) of2-chloro-4-[6-cyclopropylimidazo[1,2-a]pyridin-3-yl]pyrimidine as awhite solid.

The following compounds were prepared using a methodology similar to theone described in Preparation 20:

2-Chloro-4-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine

Preparation 21: 2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine

To a stirred solution of 2,4-dichloro-6-methylpyrimidine (246.88 mg,1.439 mmol, 1.20 equiv, 95%),2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg,1.199 mmol, 1 equiv, 95%) and K₃PO₄ (535.84 mg, 2.398 mmol, 2.00 equiv,95%) in MeCN (12.45 mL, 303.230 mmol, 187.63 equiv, 95%) and H2O (4 mL,210.932 mmol, 364.96 equiv, 95%) were added SPhos (36.27 mg, 0.084 mmol,0.07 equiv, 95%) and Pd(AcO)2 (8.50 mg, 0.036 mmol, 0.03 equiv, 95%) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for overnight at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated to a small volume. The resultingmixture was diluted with brine (20 mL). The resulting mixture wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith brine (2×20 mL), dried over anhydrous MgSO4. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (5:1)to afford 2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine (100 mg,37.78%) as a light yellow oil.

Preparation 22:2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine

Step 1: 5-(3,3-difluoroazetidin-1-yl)-2-nitropyridine. To a stirredsolution of 5-bromo-2-nitropyridine (500 mg, 2.340 mmol, 1 equiv, 95%),3,3-difluoroazetidine hydrochloride (350.95 mg, 2.574 mmol, 1.1 equiv,95%) and Cs2CO3 (4012.66 mg, 11.700 mmol, 5.00 equiv, 95%) in dioxane(37.50 mL, 425.622 mmol, 179.71 equiv, 95%) was added Pd2(dba)3 (112.78mg, 0.117 mmol, 0.05 equiv, 95%) and XantPhos (142.52 mg, 0.234 mmol,0.10 equiv, 95%) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at 100 degrees C. under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (1:1) to afford5-(3,3-difluoroazetidin-1-yl)-2-nitropyridine (200 mg, 27.81%) as alight yellow solid.

Step 2: 5-(3,3-difluoroazetidin-1-yl)pyridin-2-amine. To a stirredsolution of 543,3-difluoroazetidin-1-yl)-2-nitropyridine (175 mg, 0.569mmol, 1 equiv, 70%) in MeOH (56.00 mL, 1747.713 mmol, 2307.89 equiv,95%) was added Pd/C (318.89 mg, 2.847 mmol, 5 equiv, 95%) in portions atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for overnight at room temperature under hydrogen atmosphere. Theresulting mixture was filtered, the filter cake was washed with MeOH(3×30 mL). The filtrate was concentrated under reduced pressure. Thecrude product/resulting mixture was used in the next step directlywithout further purification.

Step 3:2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine.To a stirred solution of2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine (550 mg, 2.630 mmol,1 equiv, 95%) in H₂O (18 mL, 999.151 mmol, 379.87 equiv, 9%) and H₂O (18mL, 999.151 mmol, 379.87 equiv, 9%) was added NBS (492.78 mg, 2.630mmol, 1 equiv, 95%) at room temperature. The resulting mixture wasstirred for 1 h at room temperature. To the above mixture was added5-(3,3-difluoroazetidin-1-yl)pyridin-2-amine (666.51 mg, 3.419 mmol, 1.3equiv, 95%). The resulting mixture was stirred for additional 2.5 h at85 degrees C. The resulting mixture was diluted with EtOAc (20 mL). Themixture was neutralized to pH 7 with saturated Na2CO3 (aq.). Theresulting mixture was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (2×50 mL), dried over anhydrousMgSO4. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with CH2Cl2/MeOH (20:1). This resulted in2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine(290 mg, 31.85%) as a light yellow solid.

The following compounds were prepared using a methodology similar to theone described in Preparation 22:

2-Chloro-4-[6-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidinePreparation 23:5-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-chloropyrimidine

Step 1: 1-{imidazo[1,2-a]pyridin-6-yl}azetidine. Into a 500 mLround-bottom flask were added 6-bromoimidazo[1,2-a]pyridine (3.5 g,15.99 mmol, 1 equiv, 90%), azetidine (1441.3 mg, 23.98 mmol, 1.50 equiv,95%), toluene (300 mL, 2678.69 mmol, 167.55 equiv, 95%), BINAP (1047.9mg, 1.60 mmol, 0.10 equiv, 95%) and t-BuONa (3234.5 mg, 31.97 mmol, 2.00equiv, 95%) at room temperature. The resulting mixture was stirred forovernight at 100 degrees C. under nitrogen atmosphere. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (5:1) to afford1-[imidazo[1,2-a]pyridin-6-yl]azetidine (2.5 g, 78.72%) as a greensolid.

Step 2: 1-{3-bromoimidazo[1,2-a]pyridin-6-yl}azetidine. Into a 25 mLround-bottom flask were added 1-[imidazo[1,2-a]pyridin-6-yl]azetidine (1g, 5.03 mmol, 1 equiv, 87.2%), NBS (896.0 mg, 4.78 mmol, 0.95 equiv,95%) and DCM (60 mL, 896.61 mmol, 178.11 equiv, 95%) at roomtemperature. The resulting mixture was stirred for overnight at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (5:1) to afford1-[3-bromoimidazo[1,2-a]pyridin-6-yl]azetidine (1.1 g, 56.25%) as agreen solid.

Step 3:5-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-chloropyrimidine. To astirred solution of 1-[3-bromoimidazo[1,2-a]pyridin-6-yl]azetidine (200mg, 0.777 mmol, 1 equiv, 98%) in THF (20 mL, 234.517 mmol, 301.66 equiv,95%) was added dropwise at −10 degrees C. under N2 atmosphere.Chloro(propan-2-yl)magnesium chlorolithium (1 mL, 1.084 mmol, 1.39equiv, 17.5%) was added. The resulting mixture was stirred for 2 h at 0degrees C. under N2 atmosphere. The above mixture was added into astirred mixture of 2,4-dichloropyrimidine (182.86 mg, 1.166 mmol, 1.50equiv, 95%) and Pd(PPh₃)₄(47.28 mg, 0.039 mmol, 0.05 equiv, 95%) in THFat room temperature. The resulting mixture was stirred for additional 4h at 80 degrees C. The reaction was quenched with sat. NH₄Cl (aq.) atroom temperature. The aqueous layer was extracted with EtOAc (3×20 mL).The resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withEA:PE (1:1) to afford4-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-chloropyrimidine (120mg, 19.61%) as a green solid.

Preparation 24: 5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol

Step 1: 5-(3-Methyl-1H-pyrazol-4-yl)pyridin-3-ol. A mixture of5-bromopyridin-3-ol (10 g, 54.599 mmol, 1 equiv, 95%),Pd(dppf)Cl₂.CH₂Cl₂ (2.35 g, 2.730 mmol, 0.05 equiv, 95%), K₂CO₃ (11.91g, 81.898 mmol, 1.50 equiv, 95%) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(14.35 g, 65.518 mmol, 1.2 equiv, 95%) in dioxane (150.01 mL, 1682.194mmol, 30.81 equiv, 95%) and H2O (29.99 mL, 1664.971 mmol, 28.97 equiv,95%) was stirred for overnight at 100 degrees C. under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with CH₂Cl₂/MeOH (10:1) to afford5-(3-methyl-1H-pyrazol-4-yl)pyridin-3-ol (6.5 g, 61.16%) as a brownsolid.

Step 2: 1-Benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin-1-iumbromide. A mixture of 5-(3-methyl-1H-pyrazol-4-yl)pyridin-3-ol (6.2 g,31.851 mmol, 1 equiv, 90%) and BnBr (6.88 g, 0.038 mmol, 1.2 equiv, 95%)in MeCN (300.00 mL, 6942.365 mmol, 170.23 equiv, 95%) was stirred forovernight at 60 degrees C. under hydrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(85:15) to afford1-benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin-1-ium bromide (9g, 73.45%) as a brown solid.

Step 3:1-Benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridin-3-ol. Amixture of 1-benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin-1-iumbromide (6.5 g, 16.896 mmol, 1 equiv, 90%) and NaBH4 (2.68 g, 67.296mmol, 3.98 equiv, 95%) in EtOH (260.00 mL, 5643.864 mmol, 251.64 equiv,95%) was stirred for overnight at room temperature under nitrogenatmosphere. The reaction was quenched with sat. NH4Cl (aq.) at roomtemperature. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with CH2Cl2/MeOH (10:1) to afford1-benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridin-3-ol (5g, 98.88%) as a yellow oil.

Step 4: 5-(3-Methyl-1H-pyrazol-4-yl)piperidin-3-ol. A mixture of1-benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridin-3-ol(3.2 g, 10.692 mmol, 1 equiv, 90%) and Pd/C (1137.89 mg, 1.069 mmol,0.10 equiv, 10%) in MeOH (200.00 mL, 5929.777 mmol, 438.89 equiv, 95%)was stirred for 4 h at room temperature under hydrogen atmosphere. Theresulting mixture was filtered, the filter cake was washed with MeOH(3×5 mL). The filtrate was concentrated under reduced pressure to afford5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol (2 g, 92.88%) as a colorlesssemi-solid.

The following compounds were prepared using a methodology similar to theone described in Preparation 24:

3-(3-Fluoro-1H-pyrazol-4-yl)-5-methylpiperidine

Example 1:3-(4-(3-((S-Methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,I-4

3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(13.2 mg, 0.05 mmol), 3-((S-methylsulfonimidoyl)methyl)piperidine (8 mg,0.045 mmol), diisopropylethylamine (8 μL, 0.045 mmol) in DMF were heatedat 80° C. After 20 mins the reaction was cooled to room temperature andthe mixture was filtered and purified by reverse phase chromatography(C18; MeCN/water/0.05% TFA as eluent) to afford the trifluoroacetic acidsalt of3-(4-(3-((S-methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(12.7 mg, 40%).

The following compounds were prepared using a methodology similar to theone described in Example 1:

-   8-Methylsulfonyl-1-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]-1,8-diazaspiro[4.5]decane,    I-7-   N-[[-4,4-Difluoro-5-methyl-1-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]-3-piperidyl]methyl]methanesulfonamide,    I-8-   N-[[(2S)-4-[2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide,    I-19 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   4-[2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)morpholine,    I-20 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   6-Chloro-3-(4-(3-((methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-21 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   4-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)morpholine,    I-23 (using    6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine)-   4-[2-(6-Bromo-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)morpholine,    I-24 (using    6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine)-   N-[[1-[2-(6-Bromo-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]pyrrolidin-3-yl]methyl]methanesulfonamide    I-25 (using 6-bromo-7-fluoro-3-(4-methyl    sulfanylpyrimidin-2-yl)imidazo[1,2-a]pyridine)-   1-[2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-1,4-diazepan-5-one    I-26 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine);-   6-Chloro-3-[4-[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl]imidazo[1,2-a]pyridine    I-27 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   6-Chloro-3-[4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2-a]pyridine    I-28 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   6-Chloro-3-[4-[3-dimethylphosphoryl-5-(1H-pyrazol-4-yl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine    I-29 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   ((1-(2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ⁶-sulfanone    I-30 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   N-[[-1-[4-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide,    I-41 (using    3-(2-chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-a]pyridine);-   6-Chloro-7-fluoro-3-[4-[3-(1H-imidazol-4-yl)-2,5-dimethyl-piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2-a]pyridine    I-42 (using    6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine)-   7-[2-[6-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one    I-43 (using    3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine)-   2-(1H-Pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholine    I-44 (using    3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine)-   (3S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]piperidine-3-carboxamide    I-48 (using    6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine)-   ((1-(2-(6-Chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ⁶-sulfanone    I-49 (using (using    6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine)-   1-[2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethyl-piperidine-3-carboxamide    I-50 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine);-   1-[2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethyl-piperidine-3-carboxamide    I-51 (using    6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine)-   1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethyl-piperidine-3-carboxamide    I-52 and    1-[2-(6-chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethyl-piperidine-3-carboxamide    I-53

Example 2:1H-Pyrazol-4-yl-4-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholineand1H-pyrazol-4-yl-4-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholine,I-2 and I-3

The racemic mixture of2-(1H-pyrazol-4-yl)-4-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholine(prepared using a methodology similar to the one described in Example107) was separated by chiral supercritical fluid chromatography(conditions: OD-H, 45% MeOH, 20 mM NH3, 290 nm). The first species to beeluted was compound I-2 (99.3% ee); ESV-MS m/z 416.8 (M+H). The secondspecies to be eluted was compound I-3 (98.2% ee); ESV-MS m/z 416.4(M+H).

The following compounds were prepared using a similar methodology to theone described in Example 2:

-   7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one    I-5-   7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one,    I-6-   2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-9-   2-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-10-   Dimethyl((5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ⁶-sulfanone    I-31 and    dimethyl((5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ⁶-sulfanone    I-32-   3-[2-[2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-33 and    3-[2-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-34-   6-Chloro-3-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[12-a]pyridine    I-35 and    6-chloro-3-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2-a]pyridine    I-36-   3-[4-[2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-37 and    3-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-38-   3-[4-[3-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-39 and    3-[4-[3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine    I-40

Example 3:N-[[(2S)-4-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide,I-13

DBU (79.8 μL, 0.534 mmol) and PyBroP (124.5 mg, 0.267 mmol) were addedto a solution of2-[6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-ol (35 mg,0.134 mmol) in MeCN (700 μL). After 5 minN-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (31.1 mg, 0.160 mmol)was added and the mixture heated at 40° C. After 2 hours the reactionwas cooled to room temperature and the mixture was filtered and purifiedby reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) toafford the trifluoroacetic acid salt ofN-[[(2S)-4-[2-[6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide(28.2 mg, 45%).

The following compounds were prepared using a methodology similar to theone described in Example 3:

-   N-[[(2S)-4-[2-[6-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide,    I-1 (using    2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-1H-pyrimidin-6-one)-   1-[4-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone,    I-14-   4-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)morpholine,    I-15-   N-(((3    S,5S)-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide,    I-16-   2-(1H-Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-45

Example 4:N-[[(2S)-4-[4-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholin-2-yl]methyl]methanesulfonamide,I-17

3-Bromo-6-(difluoromethyl)imidazo[1,2-a]pyridine (70 mg, 0.283 mmol),tributyl-(2-chloropyrimidin-4-yl)stannane (137.3 mg, 0.340 mmol) andPdCl₂(PPh₃)₂(59.7 mg, 0.085 mmol) were combined in DMF (2.1 mL) anddegassed with nitrogen before heating at 120° C. To the mixture wasadded N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (27.7 mg, 0.143mmol) and diisopropylethylamine (49.6 μL, 0.285 mmol) and the reactionwas heated at 150° C. After 16 hours the reaction was cooled to roomtemperature and the mixture was filtered and purified by reverse phasechromatography (C18; MeCN/water/0.05% TFA as eluent) to afford thetrifluoroacetic acid salt ofN-[[(2S)-4-[4-[6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholin-2-yl]methyl]methanesulfonamide(6.5 mg, 5%).

The following compound was prepared using a methodology similar to theone described in Example 4:

4-[4-[6-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]-2-(1H-pyrazol-4-yl)morpholine,I-18 Example 5:1-[4-[6-[6-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone,I-11

Step 1: tert-Butyl4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylate

A mixture of 3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyridine (50 mg,0.160 mmol),tert-butyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate(62.4 mg, 0.160 mmol), dppf (8.8 mg, 0.016 mmol), Pd(OAc)₂ (1.8 mg,0.008 mmol), CuCl (15.9 mg, 0.160 mmol) and Cs₂CO₃ (156.6 mg, 0.481mmol) in DMF (1 mL) was degassed with nitrogen and heated to 90° C. for16 hours. The reaction was cooled to ambient temperature, filteredthrough a silica gel pad and concentrated under reduced pressure toafford tert-butyl4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylate;ESV-MS m/z 448.2 (M+H). The material was used without furtherpurification.

Step 2:3-(6-Piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

tert-Butyl-4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylatewas dissolved in DCM (2 mL) and TFA (1 mL, 12.98 mmol) was added. Themixture was stirred for 1 hour and then concentrated under reducedpressure. The residue was dissolved in methanol and purified by means ofan ion exchange SCX-2 cartridge to afford3-(6-piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine;ESV-MS m/z 348.1 (M+H).

Step 3:1-[4-[6-[6-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone

Acetyl chloride (15 μL, 0.208 mmol) and triethylamine (67 μL, 0.481mmol) were added to a solution of3-(6-piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridinein CH₂Cl₂ (1 mL) and stirred for 20 mins. The mixture was concentratedand purified by reverse phase chromatography (C18; MeCN/water/0.05% TFAas eluent) to afford the trifluoroacetic acid salt of1-[4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone(5.5 mg, 5%).

Example 6:2-(1H-Pyrazol-4-yl)-4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]morpholine,I-12

3-Bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine (100 mg, 0.377 mmol),2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84.2mg, 0.377 mmol), dppf (20.6 mg, 0.038 mmol), Pd(OAc)₂ (4.2 mg, 0.0189mmol), CuCl (37.4 mg, 0.377 mmol) and Cs₂CO₃ (368.8 mg, 1.132 mmol) inDMF (2 mL) were degassed with nitrogen and heated to 90° C. for 16hours. The reaction was cooled to ambient temperature and filteredthrough a silica gel pad. Diisopropylethylamine (48.8 mg, 66 μL, 0.377mmol) and 2-(1H-pyrazol-4-yl)morpholine (57.8 mg, 0.377 mmol) were addeddirectly to the filtrate and the mixture was heated at 120° C. for 16hours. The reaction mixture was cooled to ambient temperature, filteredand purified by reverse phase chromatography (C18; MeCN/water/0.05% TFAas eluent) to afford the trifluoroacetic acid salt of2-(1H-pyrazol-4-yl)-4-[6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-pyridyl]morpholine(3.1 mg, 2%).

Example 7:4-[4-(6-Chloroimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine,I-22

Step 1: 4-(4-Chloro-1,3,5-triazin-2-yl)-2-(1H-pyrazol-4-yl)morpholine

To a solution of 2,4-dichloro-1,3,5-triazine (50 mg, 0.333 mmol) anddiisopropylethylamine (128 μL, 0.734 mmol) in 1,4-dioxane (500 μL) wasadded 2-(1H-pyrazol-4-yl)morpholine (51.1 mg, 0.333 mmol). The reactionmixture was stirred for 90 mins and then was partitioned between DCM andwater, the organics extracted, dried (MgSO₄), filtered and concentratedto afford 4-(4-chloro-1,3,5-triazin-2-yl)-2-(1H-pyrazol-4-yl)morpholine;ESV-MS m/z 267.1 (M+H). The material was used without furtherpurification.

Step 2:4-[4-[(E)-2-Ethoxyvinyl]-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine

4-(4-Chloro-1,3,5-triazin-2-yl)-2-(1H-pyrazol-4-yl)morpholine wasdissolved in DME (750 μL) and2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99 mg, 0.5mmol) and Na₂CO₃ (500 μL of 2M, 1 mmol) were added. The mixture wasdegassed via vacuum/nitrogen cycles (×3), then Pd(PPh₃)₄(38.5 mg, 0.033mmol) was added and the mixture again degassed via vacuum/nitrogencycles (×3). The mixture was heated at 40° C. for 2 hours. The reactionwas purified by column chromatography (silica, EtOAc/Petroleum ethergradient) to afford4-[4-[(E)-2-ethoxyvinyl]-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine;ESV-MS m/z 303.2 (M+H).

Step 3:4-[4-(6-Chloroimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine

NBS (5.9 mg, 0.033 mmol) was added to a solution of4-[4-[(E)-2-ethoxyvinyl]-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine(10 mg, 0.033 mmol) in 1,4-dioxane (300 μL)/water (100 μL) and thereaction mixture stirred for 15 minutes. 5-Chloropyridin-2-amine (5.1mg, 0.040 mmol) was then added and the reaction mixture heated at 65° C.After 16 hours the reaction mixture was cooled to ambient temperature,filtered and purified by reverse phase chromatography (C18;MeCN/water/0.05% TFA as eluent) to afford the trifluoroacetic acid saltof4-[4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-(1H-pyrazol-4-yl)morpholine(4.9 mg, 26%).

Example 8:((1-(2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)-λ⁶-sulfanone(trans diastereomer), I-46

Step 1:6-Chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine(trans diastereomer)

A microwave vial was charged with6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine (30 mg, 0.113mmol), 2,5-dimethyl-3-(methylsulfinylmethyl)piperidine (dihydrochloridesalt) (42 mg, 0.160 mmol), DIPEA (60 μL, 0.345 mmol) and NMP (900 μL)before sealing and heating at 100° C. for 16 hours. The reaction wasallowed to cool before purifying by reverse phase chromatography (C18;MeCN/water—0.1% ammonium hydroxide as eluent) to provide6-chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine(11 mg, 45%).

Step 2:((1-(2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)-λ⁶-sulfanone(trans diastereomer)

Methanol (375 μL) was added to a mixture of6-chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine(11.2 mg, 0.144 mmol) and (diacetoxyiodo)benzene (34.7 mg, 0.108 mmol)followed by DCM (375 μL). The reaction was stirred at ambienttemperature for 3 hours. The crude reaction mixture was filtered thenpurified by reverse phase chromatography (C18; MeCN/water—0.1% ammoniumhydroxide as eluent) to give((1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)-λ⁶-sulfanone(3 mg, 19%, trans diastereomer) I-46.

The following compound was prepared using a methodology similar to theone described in Example 8:

((1-(2-(6-Chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)-λ⁶-sulfanone(cis diastereomer), I-47 Example 9:6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine,I-54

To a microwave vial containing6-chloro-3-(4-chloro-pyrimidin-2-yl)-imidazo[1,2-a]pyridine (50.00 mg;0.19 mmol; 1.00 eq.) andrac-(2r,6r)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholinehydrochloride (41.43 mg; 0.19 mmol; 1.00 eq.) was added DIPEA (0.11 ml;0.66 mmol; 3.50 eq.) and acetonitrile (2.00 ml). The reaction wasstirred at 85° C. for 2 h before the mixture was diluted in 5 mL DMSO(partially dissolved), filtered and purified with basic pre-HPLC (C18,10-90% ACN/H₂O/0.1% NH₄OH as eluent) to afford the6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine(5.0 mg, 6.4%)

The following compounds were prepared using a methodology similar to theone described in Example 9:

-   6-Chloro-3-{4-[3-(1H-imidazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine,    I-55-   3-(2-((3R,5R)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-136 (after chiral separation)-   3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-137 (after chiral separation)-   5-Methyl-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid amide, I-149-   (S)-1-[2-(6-Trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid amide, I-154-   5,5-Difluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid methyl ester, I-570

2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidineI-136 and3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,I-137 were purified by Prep-Chiral-HPLC at follows:

(2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(200 mg, 0.42 mmol, 1 equiv, 90%) was purified by Prep-Chiral-HPLC withthe following conditions (Column: Chiralpak IA, 2*25 cm, 5 um; MobilePhase A:Hex (8 mmol/L NH3.MeOH)—HPLC, Mobile Phase B: IPA-HPLC; Flowrate: 20 mL/min; Gradient: 20 B to 20 B in 25 min; 254/220 nm;RT1:11.829). This resulted in 116.2 mg (63.86%) of2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidineI-136 as a white solid.

2-[(3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine200 mg, 0.42 mmol, 1 equiv, 90%) was purified by Prep-Chiral-HPLC withthe following conditions (Column: Chiralpak IA, 2*25 cm, 5 um; MobilePhase A:Hex (8 mmol/L NH3.MeOH)—HPLC, Mobile Phase B: IPA-HPLC; Flowrate: 20 mL/min; Gradient: 20 B to 20 B in 25 min; 254/220 nm;RT2:19.149). This resulted in 117.8 mg of 2-[(3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidineI-137 as a white solid

Example 10:6-Chloro-7-fluoro-3-{4-[cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine,I-56

To a microwave vial containing6-chloro-3-(4-chloro-pyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine(50.00 mg; 0.18 mmol; 1.00 eq.) andrac-(2r,6r)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl) morpholinehydrochloride (38.80 mg; 0.18 mmol; 1.00 eq.) was added DIPEA (0.10 ml;0.62 mmol; 3.50 eq.) and acetonitrile (2.00 ml). The reaction wasstirred at 85° C. for 2 h. The white precipitate was filtered, wash withH₂O (2 mL×2), dried to afford6-chloro-7-fluoro-3-{4-[cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine(75.9 mg, 79.2%).

The following compounds were prepared using a methodology similar to theone described in Example 10:

-   6-Chloro-7-fluoro-3-{4-[3-(1H-imidazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine,    I-57-   3-{4-[(3    S,5S)-3-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine    (racemic mixture), I-60-   3-{4-[(3R,5S)-3-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine    (racemic mixture), I-61-   1-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-3-ol,    I-64-   6-Chloro-3-[4-(3-isoxazol-4-yl-piperidin-1-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine,    I-65-   6-Chloro-3-[4-(3-isoxazol-3-yl-piperidin-1-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine,    I-66-   3-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-aza-bicyclo[4.1.0]heptan-6-ol,    I-67-   4-{1-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-yl}-4-methyl-oxazolidin-2-one,    I-68-   1-Methyl-4-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-[1,4]diazepan-2-one,    I-69-   3-{4-[(3aR,6aR)-3a-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine,    I-70-   3-[4-(3-Methyl-piperidin-1-yl)-pyrimidin-2-yl]-6-trifluoromethyl-imidazo[1,2-a]pyridine,    I-71-   1-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyrrolidin-3-ol,    I-72-   6-Chloro-3-{4-[(2S,3    S)-2-(3-chloro-phenyl)-3-methyl-morpholin-4-yl]-pyrimidin-2-yl}-7-fluoro-imidazo[1,2-a]pyridine    (racemic mixture), I-73-   3-[2-(6-Trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-aza-bicyclo[4.1.0]heptan-1-ol,    I-74-   6-Chloro-3-{4-[(3    aR,6aR)-3a-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine    (racemic mixture), I-75-   1-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-piperidin-3-ol,    I-76-   (S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid (1-methyl-1H-pyrazol-4-yl)-amide, I-77-   5-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-5-aza-spiro[2.5]octane-1-carboxylic    acid, I-78-   6-Chloro-3-[4-(7,7-difluoro-6-methyl-3-aza-bicyclo[4.1.0]hept-3-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine,    I-79-   4-[2-(6-Trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-[1,4]diazepan-2-one,    I-80-   1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-phenyl-piperidin-3-ol,    I-81-   1-{1-[2-(6-Chloro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-hydroxy-piperidin-3-yl}-cyclobutanecarboxylic    acid methyl ester, I-82-   {1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-phenyl-piperidin-4-yl}-methanol,    I-83-   6-Chloro-3-[4-(1-phenyl-3-aza-bicyclo[3.1.0]hex-3-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine,    I-84-   {1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-3-phenyl-piperidin-3-yl}-methanol,    I-85

Example 11:(S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid, I-58

Step 1:(S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid

To a solution of6-Chloro-3-(4-chloro-pyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine(120.00 mg; 0.42 mmol; 1.00 eq.) and (R)-(−)-nipecotic acid (54.75 mg;0.42 mmol; 1.00 eq.) in acetonitrile (2.00 ml) was added TEA (0.15 ml;1.06 mmol; 2.50 eq.) and allowed to stir at 85° C. for 3 h. The whiteprecipitate was dried and used in the next step.

Step 2:(S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid (1H-pyrazol-4-yl)-amide

To a rbf containing(S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid (50.00 mg; 0.10 mmol; 1.00 eq.) and 1H-Pyrazol-4-ylamine (8.27 mg;0.10 mmol; 1.00 eq.) in DCM (2.00 ml) was added TEA (0.03 ml; 0.22 mmol;2.20 eq.). After stirring at rt for 2 min, 1-propanephosphonic anhydride(63.37 mg; 0.20 mmol; 2.00 eq.) was added in two portions. The reactionwas stirred at rt for 15 min before it was concentrated, diluted with 2mL MeOH/1 mL DMSO, filtered and purified with basic pre-HPLC (10-90%I/H₂O/0.1% NH₄OH as eluent) to afford(S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid (1H-pyrazol-4-yl)-amide (43.9 mg, 15.6%).

The following compounds were prepared using a methodology similar to theone described in Example 11:

-   (S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid (1-methyl-1H-pyrazol-4-yl)-amide, I-59-   (S)-1-[2-(6-Chloro-7-fluoro-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid pyridine-4-ylamide, I-86

Example 12:(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-amine,I-87

Step 1: tert-butylN-[(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-yl]carbamate

A mixture of tert-butyl N-[(3S)-piperidin-3-yl]carbamate (195.3 mg, 0.98mmol) and 6-chloro-3-(4-chloro-pyrimidin-2-yl)imidazo[1,2-a]pyridine(198.8 mg, 0.75 mmol) in DCM (3.75 mL) was added triethylamine (0.21 mL,1.50 mmol). After stirring overnight at room temperature reactionquenched with water (3 mL) and extracted with DCM (2×5 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andsolvent removed in vacuo to afford tert-butylN-[(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-yl]carbamate;ESI-MS m/z 429.2 (M+H). The material was used with our furtherpurification.

Step 2:(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-amine

N-[(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-yl}pyrimidin-4-yl)piperidin-3-yl]carbamatewas dissolved in 1,4-dioxane (3 mL) and 4H HCl in 1,4-dioxane (3 mL,35.2 mmol) was added. The mixture was stirred for 1 hour at 40° C. andthen concentrated under reduced pressure. The residue was dissolved inDMSO and purified by reverse phase chromatography (C18; MeCN/water/0.01%NH₄OH as eluent) to afford(3S)-1-(2-{6-chloroimidazo[1,2-a]pyridine-3-4-}pyrimidin-4-yl)piperidin-3-amine(72.7 mg, 29%).

Example 13:6-Chloro-7-fluoro-3-[4-(2-pyridin-2-yl-morpholin-4-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine,I-88

6-chloro-4-(4-chloro-pyrimidin-2-yl)-7-fluoro-imidazo[1,2-a]pyridine(50.0 mg, 0.18 mmol), 2-(pyridine-2-yl)morpholine (35.0 mg, 0.21 mmol),triethylamine (20 μL, 0.18 mmol) in DMF (1.0 mL) were heated at 80° C.After 14 hrs the reaction was cooled to room temperature and the mixturewas filtered and purified by reverse phase chromatography (C18;MeCN/water/0.01% NH₄OH as eluent) to afford6-chloro-7-fluoro-3-[4-(2-pyridin-2-yl-morpholin-4-yl)-pyrimidin-2-yl]-imidazo[1,2-a]pyridine(11.1 mg, 16%).

The following compounds were prepared using a methodology similar to theone described in Example 13:

-   cis-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl}morpholine,    I-93 (using    3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine)-   3-{4-[cis-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrimidin-2-yl}imidazo[1,2-a]pyridine-6-carbonitrile,    I-94 (using    3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile)-   cis-4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)morpholine,    I-95 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   2-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-octahydro-1H-pyrazino[1,2-c]pyrimidin-6-one,    I-96 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   7-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-octahydroimidazo[1,5-a]pyrazin-3-one,    I-97 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   2-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-octahydropyrazino[1,2-c][1,3]oxazin-6-one,    I-98 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   7-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4-a]pyrazin-3-one,    I-99 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   2-{6-chloroimidazo[1,2-a]pyridin-3-yl}-4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine,    I-100 (using    4-chloro-2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine)-   4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-101 (using    3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine)

Example 14:2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl}morpholine,I-89 and I-90

The racemic mixture ofcis-(2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl}morpholine(prepared using a methodology similar to the one described in Example 1)was separated by chrial supercritical fluid chromatography (conditions:IA-H, MeOH+0.5% DMEA, 2 mL/min, 220 nm). The first species to be elutedwas compound I-89 (98% ee); ESI-MS m/z 446.2 (M+H). The second speciesto be eluted was compound I-90 (98% ee); ESI-MS m/z 446.2 (M+H).

The following compounds were prepared using a similar methodology to theone described in Example 14:

-   3-{4-[(2S,6S)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimidin-2-yl}imidazo[1,2-a]pyridine-6-carbonitrile,    I-91 and    3-{4-[(2R,6R)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimidin-2-yl}imidazo[1,2-a]pyridine-6-carbonitrile,    I-92

Example 15: Exemplary Compounds I-102 to I-113

Additional compounds were prepared using similar methodologies to thosedescribed in examples I-14 above:

-   (S)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-102-   N-(((3S,5S)-1-(3-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide,    I-103-   2-(1H-pyrazol-4-yl)-4-(3-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)morpholine,    I-104-   4-(3-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)-2-(1H-pyrazol-4-yl)morpholine,    I-105-   (S)—N-((4-(3-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)morpholin-2-yl)methyl)methanesulfonamide,    I-106-   (S)—N-((4-(3-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)morpholin-2-yl)methyl)methanesulfonamide,    I-107-   2-(1H-pyrazol-4-yl)-4-(5-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-3-yl)morpholine,    I-108-   (S)—N-((4-(5-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-3-yl)morpholin-2-yl)methyl)methanesulfonamide,    I-109-   N-((1-(5-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-3-yl)piperidin-3-yl)methyl)methanesulfonamide,    I-110-   (S)—N-((4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)thiazol-2-yl)morpholin-2-yl)methyl)methanesulfonamide,    I-111-   N-((1-(3-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)piperidin-3-yl)methyl)methanesulfonamide,    I-112-   (S)—N-((4-(6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrazin-2-yl)morpholin-2-yl)methyl)methanesulfonamide,    I-113

Example 16:6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2-a]pyridine,I-114

To a 25-mL sealed tube, was placed2-chloro-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(200.000 mg, 0.60 mmol, 1.00 equiv, 90%),3-methyl-5-(1H-pyrazol-4-yl)piperidine (110.658 mg, 0.60 mmol, 1.00equiv, 90%), DIEA (163.993 mg, 1.21 mmol, 2.00 equiv, 95%), i-propanol(10.000 mL, 124.30 mmol, 206.24 equiv, 95%). The resulting solution wasstirred for overnight at 100° C. The resulting mixture was concentratedunder vacuum. The crude product (300 mg) was purified by Prep-HPLC withthe following conditions (Prep-HPLC-015): Column, XBridge Shield RP18OBD Column, 30*150 mm, 5 um; mobile phase, Water (10 MMOL/L NH₄HCO₃+0.1%NH₃.H₂O) and ACN (43.0% ACN up to 47.0% in 9 min); Detector, uv 254 nm.This resulted in 23.9 mg (9%) of2-[3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidineI-114 as a white solid.

The following compounds were prepared using a methodology similar to theone described in Example 16:

-   cis-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholine,    I-115-   cis-2-Methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholine,    I-117-   3-{4-[cis-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine,    I-119

TABLE 2 Analytical data for compounds of formula I LCMS Cmpd LCMS (rt,No. (ES+) min) ¹H NMR I-1 457.2 2.46 (500 MHz, Methanol-d4) δ 10.40 (s,1H), 8.71 (s, 1H), 8.34 (d, 1H), 8.03 (d, 1H), 7.93 (dd, 1H), 6.91 (d,1H), 4.58-4.34 (m, 1H), 4.13 (ddd, 1H), 3.80-3.68 (m, 2H), 3.22-3.12 (m,1H), 2.99 (s, 3H) I-2 416.8 2.37 (500 MHz, DMSO-d6) δ 10.33 (s, 1H),8.65 (s, 1H), 8.42 (d, 1H), 7.99 (d, 1H), 7.75 (dd, 1H), 7.69 (s, 2H),6.95 (d, 1H), 4.60 (dd, 1H), 4.08-4.01 (m, 1H), 3.23 (dd, 2H) I-3 416.42.37 (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 8.42 (d, 1H),7.99 (d, 1H), 7.75 (dd, 1H), 7.69 (s, 2H), 6.95 (d, 1H), 4.60 (dd, 1H),4.08-4.01 (m, 1H), 3.23 (dd, J = 13.1, 10.6 Hz, 2H) I-4 439.2 2.41 (500MHz, DMSO-d6) δ 10.43-10.36 (m, 1H), 8.61 (d, 1H), 8.40 (dd, 1H), 7.97(dt, 1H), 7.72 (dd, 1H), 6.79 (d, 1H), 3.90-3.66 (m, 2H), 3.62 (d, 3H),3.37-3.08 (m, 2H), 2.36 (d, 1H), 2.02 (s, 1H), 1.79 (s, 1H), 1.68-1.47(m, 2H) I-5 404.5 2.24 (500 MHz, Methanol-d4) δ 10.38-10.32 (m, 1H),8.75 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 6.99 (d, 1H),4.79-4.65 (m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88 (m, 2H), 3.65 (dd, 1H),3.29-3.17 (m, 3H), 3.12 (ddd, 1H) I-6 404.4 2.24 (500 MHz, Methanol-d4)δ 10.38-10.32 (m, 1H), 8.75 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.94(dd, 1H), 6.99 (d, 1H), 4.79-4.65 (m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88(m, 2H), 3.65 (dd, 1H), 3.29-3.17 (m, 3H), 3.12 (ddd, 1H) I-7 481.2 3.13(500 MHz, DMSO-d6) δ 10.47 (d, 1H), 8.47 (s, 1H), 8.36 (d, 1H), 7.96 (d,1H), 7.70 (dd, 1H), 6.48 (s, 2H), 3.72-3.65 (m, 6H), 2.95 (s, 3H), 2.88(dd, 2H), 2.16-2.08 (m, 2H), 1.96 (p, 2H), 1.51 (d, 2H) I-8 398.1 1.47(400 MHz, d4-MeOH) δ 8.81 (d, 1H), 7.16 (d, 1H), 3.98 (dd, 1H), 3.76(dt, 1H), 3.50 (dd, 1H), 3.35 (ddd, 1H), 2.68 (tt, 1H), 2.05 (dt, 1H),1.88-1.58 (m, 3H) I-9 416.1 2.39 (500 MHz, Methanol-d4) δ 10.50 (s, 1H),8.56 (s, 1H), 8.44 (d, 1H), 7.89 (d, 1H), 7.73 (br s, 2H) 7.70 (dd, 1H),7.26 (d, 1H), 4.74-4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd, 1H), 3.87 (td,1H), 3.37-3.28 (m, 2H) I-10 416.3 2.38 (500 MHz, Methanol-d4) δ 10.50(s, 1H), 8.56 (s, 1H), 8.44 (d, 1H), 7.89 (d, 1H), 7.74 (br s, 2H), 7.70(dd, 1H), 7.26 (d, 1H), 4.74-4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd, 1H),3.87 (td, 1H), 3.37-3.28 (m, 2H) I-11 390.1 2.65 (500 MHz, Methanol-d4)δ 10.66 (s, 1H), 8.58 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.77 (dd,1H), 7.37 (d, 1H), 6.94 (d, 1H), 3.84-3.68 (m, 8H), 2.20 (s, 3H) I-12415.2 2.6 (500 MHz, DMSO-d6) δ 10.35 (dt, 1H), 8.47 (s, 1H), 7.89 (dt,1H), 7.76 (s, 1H), 7.72 (dd, 1H), 7.58 (dd, 1H), 7.53 (s, 1H), 7.39 (d,1H), 6.92 (d, 1H), 4.63 (dd, 1H), 4.30-4.22 (m, 1H), 4.13-4.00 (m, 2H),3.78 (td, 1H), 3.10 (td, 1H), 3.05 (dd, 1H) I-13 439.1 2.18 (500 MHz,Methanol-d4) δ 10.18 (tt, 1H), 8.45 (s, 1H), 8.30 (d, 1H), 7.78 (dd,1H), 7.60 (dd, 1H), 7.03 (t, 1H), 6.65 (d, 1H), 4.41 (s, 1H), 4.27 (d,1H), 4.12 (ddd, 1H), 3.78-3.66 (m, 2H), 3.30 (dd, 1H), 3.22-3.14 (m,2H), 3.05 (s, 3H), 2.95 (dd, 1H) I-14 373.1 2.12 (500 MHz, DMSO-d6) δ10.17 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.96 (dd, 1H), 7.72 (dd, 1H),7.31 (t, 1H), 6.87 (d, 1H), 3.88-3.81 (m, 2H), 3.81-3.74 (m, 2H),3.65-3.60 (m, 4H), 2.08 (s, 3H) I-15 398.1 2.16 (500 MHz, DMSO-d6) δ10.18 (d, 1H), 8.64 (s, 1H), 8.40 (d, 1H), 7.94 (d, 1H), 7.75-7.64 (m,3H), 7.24 (t, 1H), 6.93 (d, 1H), 4.60 (dd, 1H), 4.09-4.00 (m, 1H), 3.72(td, 1H), 3.26-3.16 (m, 1H) I-16 487.2 2.71 — I-17 439.1 2.25 (500 MHz,Methanol-d4) δ 10.38 (dd, 1H), 8.83 (s, 1H), 8.47 (d, 1H), 8.11-7.99 (m,2H), 7.27 (d, 1H), 7.15 (td, 1H), 4.60 (ddd, 1H), 4.50 (dt, 1H), 4.10(ddd, 1H), 3.77-3.64 (m, 2H), 3.30-3.22 (m, 2H), 3.05 (dd, 1H), 2.99 (s,3H) I-18 398.1 2.2 (500 MHz, Methanol-d4) δ 10.38 (d, 1H), 8.86 (s, 1H),8.50 (d, 1H), 8.13-7.98 (m, 2H), 7.76 (s, 2H), 7.29 (d, 1H), 7.01 (t,1H), 4.71 (dt, 2H), 4.59-4.51 (m, 1H), 4.14 (ddd, 1H), 3.86 (td, 1H),3.43-3.32 (m, −2H) I-19 423.1 2.3 (500 MHz, Methanol-d4) δ 10.13 (dd,1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.95 (dd, 1H), 7.92 (dd, 1H), 6.91 (d,1H), 4.54 (s, 1H), 4.36 (s, 1H), 4.19-4.08 (m, 1H), 3.79-3.66 (m, 2H),3.34 (d, 3H), 3.13 (dd, 1H), 2.99 (s, 3H) I-20 382.1 2.24 (500 MHz,DMSO-d6) δ 10.02 (d, 1H), 8.60 (s, 1H), 8.41 (d, 1H), 7.87 (d, 1H), 7.70(s, 2H), 7.63 (dd, 1H), 6.92 (d, 1H), 4.60 (dd, 1H), 4.05 (dd, 1H), 3.71(td, 1H), 3.22 (td, 2H) I-21 405.1 2.26 (500 MHz, DMSO-d6) δ 10.03 (dd,1H), 8.56 (d, 1H), 8.38 (dd, 1H), 7.86 (d, 1H), 7.61 (dd, 1H), 6.80(dd1H), 3.94-3.68 (m, 2H), 3.64 (d, 3H), 3.23 (dd, 2H), 2.44-2.32 (m,1H), 2.02 (d, 1H), 1.85-1.73 (m, 1H), 1.67-1.45 (m, 2H) I-22 383.1 2.23(500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.74 (s, 1H), 8.66 (d, 1H), 7.87 (d,1H), 7.69 (d, 2H), 7.63 (d, 1H), 4.80-4.65 (m, 1H), 4.65-4.48 (m, 2H),4.11-3.96 (m, 1H), 3.68 (d, 1H) I-23 400.1 2.36 (500 MHz, DMSO-d6) δ12.81 (s, 1H), 10.14 (d, 1H), 8.45 (d, 1H), 8.38 (dd, 1H), 7.91 (d, 1H),7.70 (s, 2H), 6.86 (d, 1H), 4.59 (dd, 1H), 4.56-4.15 (m, 2H), 4.12-4.01(m, 1H), 3.71 (td, 1H), 3.24-3.09 (m, 2H) I-24 446 2.35 (500 MHz,DMSO-d6) δ 10.20 (d, 1H), 8.51 (s, 1H), 8.40 (d, 1H), 7.92 (d, 1H), 7.70(s, 2H), 6.90 (d, 1H), 4.59 (dd, 1H), 4.09-4.00 (m, 1H), 3.70 (dd, 1H),3.28-3.12 (m, 2H) I-25 469.1 2.5 (500 MHz, DMSO-d6) δ 10.35 (d, 1H),8.39 (s, 1H), 8.29 (d, 1H), 7.88 (d, 1H), 7.22 (d, 1H), 6.43 (s, 1H),3.81-3.42 (m, 5H), 3.10-3.02 (m, 2H), 2.93 (s, 3H), 2.17 (s, 1H), 1.84(s, 1H) I-26 343.1 2.0 (400 MHz, DMSO-d6) δ 10.04-9.98 (m, 1H), 8.47 (s,1H), 8.37 (d, J = 6.2 Hz, 1H), 7.85-7.77 (m, 1H), 7.69 (t, J = 5.6 Hz,1H), 7.52 (dd, J = 9.5, 2.1 Hz, 1H), 6.80 (d, J = 6.3 Hz, 1H), 3.91 (s,4H), 3.30 (s, 3H), 2.62 (d, J = 6.8 Hz, 2H). I-27 366.1 2.42 (400 MHz,DMSO-d6) δ 12.68 (s, 1H), 10.13 (dd, J = 2.2, 0.9 Hz, 1H), 8.42 (s, 1H),8.28 (d, J = 5.9 Hz, 1H), 7.79 (dd, J = 9.5, 0.9 Hz, 1H), 7.69 (s, 1H),7.49 (dd, J = 9.6, 2.1 Hz, 2H), 6.43 (d, J = 6.1 Hz, 1H), 3.85 (d, J =30.4 Hz, 1H), 3.63 (d, J = 35.1 Hz, 1H), 3.49 (d, J = 8.0 Hz, 2H), 2.42(d, J = 18.1 Hz, 1H), 2.05 (s, 1H), 0.99-0.90 (m, 1H). I-28 381.1 2.0 —I-29 456.1 1.89 — I-30 405.1 2.25 (400 MHz, DMSO-d6) δ 10.04 (dd, J =2.1, 0.8 Hz, 1H), 8.42 (s, 1H), 8.31 (d, J = 6.3 Hz, 1H), 7.79 (dd, J =9.5, 0.8 Hz, 1H), 7.49 (dd, J = 9.5, 2.2 Hz, 1H), 6.71 (d, J = 6.3 Hz,1H), 3.30 (s, 2H), 3.05 (d, J = 0.9 Hz, 3H), 3.02 (d, J = 1.0 Hz, 3H),2.97 (d, J = 3.4 Hz, 1H), 2.86 (s, 2H), 1.91 (dd, J = 9.1, 4.9 Hz, 1H),1.77 (d, J = 11.5 Hz, 1H), 1.50 (t, J = 9.4 Hz, 2H). I-31 453.1 2.55(500 MHz, Methanol-d4) δ 10.33 (s, 1H), 8.39 (s, 1H), 8.15 (d, 1H), 7.74(d, 1H), 7.54 (dd, 1H), 6.56 (d, 1H), 4.40 (br s, 2H), 3.22 (masked,1H), 3.04 (d, 6H), 2.98 (s, 1H), 2.60 (m, 1H), 2.43 (m, 1H), 1.93 (m,1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd, 1H), 0.93 (d, 3H). I-32 453.12.55 (500 MHz, Methanol-d4) δ 10.33 (s, 1H), 8.39 (s, 1H), 8.15 (d, 1H),7.74 (d, 1H), 7.54 (dd, 1H), 6.56 (d, 1H), 4.40 (br s, 2H), 3.22(masked, 1H), 3.04 (d, 6H), 2.98 (s, 1H), 2.60 (m, 1H), 2.43 (m, 1H),1.93 (m, 1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd, 1H), 0.93 (d, 3H).I-33 443.1 2.37 — I-34 443.1 2.37 (500 MHz, Methanol-d4) δ 10.60-10.22(m, 1H), 8.53 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 9.5 Hz,1H), 7.73 (s, 2H), 7.68 (d, J = 9.3 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H),5.05 (s, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 3.29-3.19 (m, 1H), 2.99 (s,1H), 1.38 (d, J = 6.3 Hz, 3H), 1.32-0.97 (m, 3H). I-35 409.1 2.29 (500MHz, DMSO-d6) δ 12.59 (s, 1H), 10.05 (m, 1H), 8.45 (m, 1H), 8.36 (m,1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 6.79 (m, 1H), 5.03-4.60(m, 1H), 4.23-3.83 (m, 2H), 2.92 (m, 1H), 2.76 (m, 1H), 2.51 (m, 1H),1.19 (m, 3H), 0.99 (m, 3H). I-36 409.3 2.48 (500 MHz, DMSO-d6) δ 12.59(s, 1H), 10.05 (m, 1H), 8.45 (m, 1H), 8.36 (m, 1H), 7.95 (d, 1H), 7.80(d, 1H), 7.61 (d, 1H), 6.79 (m, 1H), 5.03-4.60 (m, 1H), 4.23-3.83 (m,2H), 2.92 (m, 1H), 2.76 (m, 1H), 2.51 (m, 1H), 1.19 (m, 3H), 0.99 (m,3H). I-37 443.4 2.45 (500 MHz, DMSO-d6) δ 10.41 (m, 1H), 8.54 (s, 1H),8.35 (d, 1H), 7.96 (d, 1H), 7.66-7.61 (m, 3H), 6.85 (m, 1H), 5.92-5.45(m, 1H), 4.06 (m, 1H), 2.89 (m, 1H), 2.80-2.65 (m, 1H), 2.55 (m, 1H),1.18 (m, 3H), 0.98 (m, 3H). I-38 443.4 2.45 — I-39 429.4 2.35 (500 MHz,Methanol-d4) δ 10.37 (s, 1H), 8.47 (s, 1H), 8.27 (d, 1H), 7.82 (d, 1H),7.76 (s, 1H), 7.64 (d, 1H), 6.72 (d, 1H), 4.47 (s, 2H), 4.00 (d, 1H),3.07-2.97 (m, 2H), 1.26 (d, 3H). I-40 429.4 2.35 — I-41 487.3 2.79 (500MHz, DMSO-d6) δ 10.11 (s, 1H), 8.67 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H),7.92 (d, J = 9.6 Hz, 1H), 7.62 (dd, J = 9.3, 1.7 Hz, 1H), 7.33 (d, J =5.3 Hz, 1H), 7.25 (t, J = 55.8 Hz, 1H), 7.25 (s, 1H), 5.12 (d, J = 15.6Hz, 1H), 4.73 (d, J = 15.0 Hz, 1H), 3.47-3.42 (m, 1H), 3.01-2.84 (m,3H), 2.96 (s, 3H), 2.23 (s, 2H), 1.07 (d, J = 6.6 Hz, 3H). I-42 427.82.2 (500 MHz, Methanol-d4) δ 10.39-10.32 (m, 1H), 8.72 (d, J = 7.0 Hz,1H), 8.53-8.38 (m, 2H), 7.84-7.78 (m, 1H), 7.59 (d, J = 18.5 Hz, 1H),6.94 (dd, J = 18.3, 6.5 Hz, 1H), 5.33 (s, 1H), 5.14 (d, J = 4.4 Hz, 1H),4.89 (d, J = 4.1 Hz, 1H), 4.45 (d, J = 14.7 Hz, 1H), 4.09 (dq, J = 6.7,3.8 Hz, 1H), 3.80 (dd, J = 14.8, 3.4 Hz, 1H), 3.65-3.54 (m, 1H), 3.29(d, J = 14.1 Hz, 1H), 1.56 (dd, J = 6.7, 2.1 Hz, 3H), 1.31 (dd, J =12.3, 7.0 Hz, 3H). I-43 404.1 2.24 (500 MHz, Methanol-d4) δ 10.38-10.32(m, 1H), 8.75 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 9.4 Hz,1H), 7.94 (dd, J = 9.4, 1.8 Hz, 1H), 6.99 (d, J = 6.9 Hz, 1H), 4.79-4.65(m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88 (m, 2H), 3.65 (dd, J = 9.5, 8.4Hz, 1H), 3.29-3.17 (m, 3H), 3.12 (ddd, J = 13.3, 12.0, 3.4 Hz, 1H). I-44416.1 2.37 (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.73 (s, 1H), 8.47 (d, J= 5.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.65 (s,2H), 7.34 (d, J = 5.3 Hz, 1H), 4.63-4.54 (m, 2H), 4.46 (d, J = 13.3 Hz,1H), 4.07-3.99 (m, 1H), 3.72 (td, J = 11.6, 2.9 Hz, 1H), 3.22 (d, J =11.8 Hz, 1H). I-45 416.2 2.33 (500 MHz, Methanol-d4) δ 10.29 (s, 1H),8.77 (s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.06 (dt, J = 9.5, 0.8 Hz, 1H),7.97 (dd, J = 9.4, 1.8 Hz, 1H), 7.76 (s, 2H), 7.05 (d, J = 7.2 Hz, 1H),4.76 (dd, J = 10.6, 2.7 Hz, 1H), 4.19 (ddd, J = 11.8, 3.8, 1.6 Hz, 1H),3.88 (td, J = 11.8, 2.8 Hz, 1H), 3.59-3.41 (m, 2H). I-46 433.3 2.53 —I-47 433.2 2.53 — I-48 377.1 2.19 (500 MHz, Methanol-d4) δ 10.01 (d, J =7.0 Hz, 1H), 8.62 (s, 1H), 8.22 (d, J = 7.3 Hz, 1H), 7.82 (dd, J = 8.7,0.6 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.76(dd, J = 13.5, 9.4 Hz, 1H), 3.60 (t, J = 11.7 Hz, 1H), 2.71 (tt, J =9.4, 4.1 Hz, 1H), 2.21-2.12 (m, 1H), 2.08-1.94 (m, 2H), 1.83-1.71 (m,1H). I-49 423.0 2.29 (500 MHz, Methanol-d4) δ 10.12 (d, J = 6.9 Hz, 1H),8.63 (s, 1H), 8.29 (dd, J = 7.0, 0.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H),6.96 (d, J = 7.1 Hz, 1H), 4.50 (s, 1H), 4.19 (s, 1H), 3.89 (tt, J = 8.5,3.9 Hz, 1H), 3.61-3.59 (m, 7H), 3.55 (dd, J = 13.2, 8.6 Hz, 1H),2.25-2.16 (m, 1H), 2.05 (ddq, J = 13.4, 6.9, 3.9, 3.4 Hz, 1H), 1.90-1.76(m, 2H). I-50 385.1 2.32 (500 MHz, Methanol-d4) δ 10.05 (dd, J = 2.0,0.9 Hz, 1H), 8.70 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.93 (dd, J = 9.5,0.8 Hz, 1H), 7.85 (dd, J = 9.5, 2.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H),5.37 (s, 1H), 4.06 (s, 1H), 3.59 (dd, J = 13.9, 3.2 Hz, 1H), 3.04 (dt, J= 12.7, 4.5 Hz, 1H), 2.40-2.29 (m, 2H), 1.68-1.61 (m, 1H), 1.39 (d, J =6.9 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). I-51 385.1 2.38 (500 MHz,Methanol-d4) δ 10.04 (s, 1H), 8.71 (s, 1H), 8.29 (d, J = 7.1 Hz, 1H),7.94 (dd, J = 9.7, 0.9 Hz, 1H), 7.87 (dd, J = 9.5, 2.0 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 2.96 (s, 1H), 2.80 (d, J = 11.6 Hz, 1H), 1.89 (s, 1H),1.77 (t, J = 11.9 Hz, 2H), 1.35 (d, J = 6.9 Hz, 3H), 1.17 (s, 3H). I-52403.1 2.41 (500 MHz, Methanol-d4) δ 10.06 (d, J = 7.0 Hz, 1H), 8.65 (s,1H), 8.25 (d, J = 7.3 Hz, 1H), 7.84 (dd, J = 8.7, 0.6 Hz, 1H), 7.02 (d,J = 7.3 Hz, 1H), 5.39 (s, 1H), 4.07 (s, 1H), 3.62 (dd, J = 13.7, 3.3 Hz,1H), 3.04 (dt, J = 12.8, 4.7 Hz, 1H), 2.43-2.27 (m, 2H), 1.71-1.61 (m,1H), 1.40 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). I-53 403.1 2.471H NMR (500 MHz, Methanol-d4) δ 10.06 (d, J = 7.0 Hz, 1H), 8.66 (s, 1H),8.26 (d, J = 7.2 Hz, 1H), 7.84 (dd, J = 8.8, 0.6 Hz, 1H), 7.05 (d, J =7.3 Hz, 1H), 5.66 (s, 1H), 4.06 (s, 1H), 2.99 (s, 2H), 2.87-2.77 (m,1H), 1.89 (s, 1H), 1.77 (q, J = 12.0 Hz, 2H), 1.36 (s, 3H), 1.17 (s,3H). I-54 412 1.92 (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.61-8.37 (m,2H), 7.81 (d, 1H), 7.52 (d, 1H), 6.89 (d, 1H), 5.08 (dd, 1H), 3.92 (t,2H), 2.86 (t, 1H), 2.41 (s, 3H), 1.44 (s, 1H), 1.28 (d, 3H). I-55 3800.89 (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.0 (s, 1H), 8.43 (m, 2H),7.76 (d, 1H), 7.51 (m, 2H), 6.88 (m, 2H), 3.07 (m, 2H), 2.76 (s, 1H),2.03 (m, 1H), 1.55 (m, 3H). I-56 430 2.22 (400 MHz, DMSO-d6) δ 8.48 (s,1H), 8.41 (d, 1H), 7.92 (d, 1H), 6.89 (d, 1H), 5.07 (dd, 1H), 4.01-3.70(m, 1H), 2.84 (dd, 1H), 2.41 (s, 3H), 2.08 (s, 1H), 1.28 (d, 3H). I-57398 0.98 (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 10.12 (d, 1H), 8.50-8.16(m, 2H), 7.89 (d, 1H), 7.58 (s, 1H), 6.96-6.59 (m, 2H), 3.11 (dd, 2H),2.77 (dq, 1H), 2.15-2.01 (m, 1H), 1.89-1.67 (m, 2H), 1.60 (dd, 1H). I-58441 1.27 (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.02 (s, 1H), 8.52-8.11(m, 2H), 7.90 (d, 1H), 7.68 (s, 2H), 6.83 (d, 1H), 3.22 (dd, 1H), 3.07(t, 1H), 2.63-2.52 (m, 1H), 1.99 (d, 1H), 1.92-1.65 (m, 2H), 1.50 (d,1H). I-59 455 1.40 (400 MHz, DMSO-d6) δ 10.14 (d, 1H), 10.01 (s, 1H),8.41 (s, 1H), 8.32 (d, 1H), 7.97-7.72 (m, 2H), 7.39 (s, 1H), 6.83 (d,1H), 3.78 (s, 3H), 3.22 (dd, 1H), 3.08 (t, 1H), 1.98 (d, 1H), 1.82 (s,2H), 1.51 (t, 1H). I-60 442 1.84 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s,1H), 8.53 (s, 1H), 8.30 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H),7.67 (d, J = 9.4 Hz, 1H), 7.49 (d, J = 39.5 Hz, 1H), 7.39-7.19 (m, 2H),6.82 (d, J = 6.1 Hz, 1H), 3.74 (s, 4H), 3.47 (s, 1H), 3.05 (s, 1H),2.05-1.87 (m, 2H), 1.72 (d, J = 10.6 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H).I-61 442 1.91 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (s, 1H),8.32 (d, J = 6.2 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.82-7.54 (m, 2H),7.40 (s, 1H), 6.87 (d, J = 6.3 Hz, 1H), 3.80 (s, 3H), 2.79 (t, J = 12.1Hz, 1H), 2.68 (t, J = 13.1 Hz, 1H), 2.58 (t, J = 12.3 Hz, 1H), 2.05 (d,J = 12.8 Hz, 1H), 1.71 (s, 1H), 1.31 (q, J = 11.9 Hz, 1H), 1.00 (d, J =6.4 Hz, 3H). I-62 412 I-63 412 I-64 398 1.65 1H NMR (400 MHz, DMSO-d6) δ10.10 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.80 (d, J = 9.9 Hz, 1H),7.51 (d, J = 9.5 Hz, 1H), 6.64 (s, 1H), 6.50 (s, 1H), 4.27-3.56 (m, 5H),2.56 (s, 1H), 2.39 (s, 3H). I-65 381 1.59 1H NMR (400 MHz, DMSO-d6) δ10.00 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.79(d, J = 9.5 Hz, 1H), 7.49 (d, J = 10.1 Hz, 2H), 6.78 (dd, J = 16.5, 6.3Hz, 1H), 4.43 (s, 2H), 3.00 (q, J = 16.5, 14.9 Hz, 1H), 2.94-2.76 (m,1H), 1.82 (d, J = 12.5 Hz, 2H), 1.68-1.42 (m, 2H). I-66 381 1.65 1H NMR(400 MHz, DMSO-d6) δ 9.98 (dd, J = 2.2, 0.9 Hz, 1H), 8.86 (d, J = 1.6Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.78 (dd, J = 9.5, 0.8Hz, 1H), 7.48 (dd, J = 9.5, 2.2 Hz, 1H), 6.83 (d, J = 6.3 Hz, 1H), 6.68(d, J = 1.7 Hz, 1H), 4.58 (s, 1H), 4.34 (s, 1H), 3.22 (ddd, J = 13.6,11.4, 2.8 Hz, 1H), 3.03 (tt, J = 10.4, 3.9 Hz, 1H), 2.12 (d, J = 10.0Hz, 1H), 1.84 (dtd, J = 13.9, 10.3, 9.3, 4.2 Hz, 2H), 1.63 (q, J = 12.9Hz, 1H). I-67 342 1.22 1H NMR (400 MHz, DMSO-d6) δ 10.13-9.94 (m, 1H),8.41 (d, J = 3.0 Hz, 1H), 8.31 (d, J = 6.2 Hz, 1H), 7.79 (d, J = 9.9 Hz,1H), 7.50 (d, J = 9.2 Hz, 1H), 6.63 (d, J = 6.3 Hz, 1H), 5.70 (d, J =2.5 Hz, 1H), 4.37 (s, 1H), 3.68 (d, J = 13.1 Hz, 2H), 2.13 (s, 1H), 1.68(d, J = 10.3 Hz, 1H), 1.21 (s, 1H), 0.75 (d, J = 9.4 Hz, 1H), 0.36 (d, J= 5.0 Hz, 1H). I-68 413 1.38 1H NMR (400 MHz, DMSO-d6) δ 10.04 (d, J =8.7 Hz, 1H), 8.52 (s, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.06 (s, 1H), 7.80(d, J = 9.4 Hz, 1H), 7.55-7.43 (m, 1H), 6.77 (d, J = 6.4 Hz, 1H), 4.45(s, 2H), 4.25 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 9.9 Hz, 1H), 2.92 (t, J= 12.3 Hz, 1H), 2.74 (t, J = 12.5 Hz, 1H), 1.79 (dd, J = 21.9, 11.6 Hz,2H), 1.58 (d, J = 11.5 Hz, 1H), 1.39 (dt, J = 23.5, 14.1 Hz, 2H), 1.29(d, J = 11.8 Hz, 3H). I-69 390 1.57 1H NMR (400 MHz, DMSO-d6) δ 10.41(s, 1H), 8.55 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.95 (d, J= 9.5 Hz, 1H), 7.68 (d, J = 9.5 Hz, 1H), 6.72 (s, 1H), 4.41 (s, 2H),3.94 (dd, J = 47.0, 23.2 Hz, 2H), 3.57 (s, 2H), 2.81 (s, 3H), 1.85 (s,2H). I-70 484 2.65 ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.52 (d, J= 1.5 Hz, 1H), 8.34 (dd, J = 6.1, 1.5 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H),7.67 (d, J = 9.5 Hz, 1H), 6.52 (d, J = 6.1 Hz, 1H), 4.25 (s, 1H), 3.89(s, 2H), 3.19 (s, 1H), 3.12-2.94 (m, 1H), 2.30 (dt, J = 14.3, 7.7 Hz,1H), 2.12 (dq, J = 16.2, 8.8, 7.9 Hz, 2H), 1.92 (ddp, J = 34.3, 13.4,7.0, 6.5 Hz, 2H), 1.72 (dt, J = 13.0, 6.4 Hz, 1H), 1.26 (s, 6H). I-71362 2.43 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.51 (d, J = 1.3 Hz,1H), 8.30 (dd, J = 6.4, 1.4 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.67 (d,J = 9.3 Hz, 1H), 6.78 (d, J = 6.3 Hz, 1H), 4.33 (s, 1H), 3.02 (t, J =12.0 Hz, 1H), 1.79 (dd, J = 33.2, 13.3 Hz, 2H), 1.70-1.41 (m, 2H),1.41-1.17 (m, 1H), 0.95 (d, J = 6.5 Hz, 3H). I-72 425 1.6 1H NMR (400MHz, DMSO-d6) δ 10.14 (d, J = 19.7 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H),8.31 (dd, J = 16.7, 6.1 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.79 (s, 1H),7.50 (s, 1H), 6.46 (dd, J = 19.6, 6.0 Hz, 1H), 5.80 (d, J = 20.5 Hz,1H), 4.84 (p, J = 6.9 Hz, 1H), 3.89 (dt, J = 45.7, 12.7 Hz, 3H), 3.66(d, J = 10.1 Hz, 2H), 2.31 (s, 1H), 1.51 (d, J = 6.7 Hz, 7H). I-73 4592.8 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J = 7.5 Hz, 1H), 8.47 (s, 1H),8.40 (d, J = 6.2 Hz, 1H), 7.90 (d, J = 9.8 Hz, 1H), 7.48 (s, 1H),7.44-7.25 (m, 3H), 6.84 (d, J = 6.3 Hz, 1H), 5.14 (d, J = 7.1 Hz, 1H),4.85 (d, J = 2.2 Hz, 1H), 4.21-3.97 (m, 1H), 3.78 (dd, J = 11.2, 4.1 Hz,1H), 3.55 (td, J = 11.5, 3.7 Hz, 1H), 3.42 (td, J = 12.6, 4.3 Hz, 1H),1.41 (d, J = 6.6 Hz, 3H). I-74 376 1.44 1H NMR (400 MHz, DMSO-d6) δ10.42 (s, 1H), 8.51 (s, 1H), 8.31 (d, J = 6.1 Hz, 1H), 7.94 (d, J = 9.4Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 6.66 (d, J = 6.2 Hz, 1H), 5.69 (d, J= 2.6 Hz, 1H), 4.34 (s, 1H), 3.68 (d, J = 13.1 Hz, 2H), 2.22-2.04 (m,1H), 1.76-1.50 (m, 1H), 1.22 (s, 1H), 0.76 (dd, J = 10.3, 5.1 Hz, 1H),0.36 (t, J = 5.1 Hz, 1H). I-75 450 2.29 1H NMR (400 MHz, DMSO-d6) δ10.03 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 9.4Hz, 1H), 7.61-7.31 (m, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.18 (d, J = 35.3Hz, 1H), 3.86 (s, 2H), 3.17 (d, J = 8.8 Hz, 1H), 3.04 (p, J = 7.1 Hz,1H), 2.30 (dt, J = 14.7, 7.7 Hz, 1H), 2.12 (dp, J = 16.1, 8.0, 7.5 Hz,2H), 2.04-1.76 (m, 2H), 1.72 (dt, J = 13.1, 6.6 Hz, 1H), 1.36-1.13 (m,6H). I-76 439 1.3 1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 8.4 (s, 1H),8.25 (d, 1H), 8.16 (s, 1H), 7.76 (d, 1H), 7.51 (d, 1H), 6.77 (d, 1H),5.25 (s, 1H), 4.75 (m, 1H), 3.70 (m, 1H), 2.22 (m, 1H), 1,92 (m, 2H),1.61 (m, 1H), 1.46 (m, 6H). I-77 455 1.4 1H NMR (400 MHz, DMSO-d6) δ10.14 (d, J = 7.6 Hz, 1H), 10.01 (s, 1H), 8.41 (s, 1H), 8.32 (d, J = 6.3Hz, 1H), 7.97-7.72 (m, 2H), 7.39 (s, 1H), 6.83 (d, J = 6.3 Hz, 1H), 3.78(s, 3H), 3.22 (dd, J = 13.2, 10.9 Hz, 1H), 3.08 (t, J = 12.4 Hz, 1H),1.98 (d, J = 11.8 Hz, 1H), 1.82 (s, 2H), 1.51 (t, J = 12.9 Hz, 1H). I-78384 1.39 1H NMR (400 MHz, DMSO-d6) δ 10.03 (d, J = 13.8 Hz, 1H), 8.45(s, 1H), 8.29 (t, J = 6.5 Hz, 1H), 7.78 (dd, J = 9.8, 5.5 Hz, 1H), 7.49(d, J = 9.6 Hz, 1H), 6.84-6.47 (m, 1H), 1.93-1.46 (m, 5H), 1.22-0.98 (m,1H), 0.91 (dt, J = 13.2, 4.6 Hz, 1H). Several peaks overlap with solventpeak. I-79 376 2.0 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.51-8.16(m, 2H), 7.78 (d, J = 9.5 Hz, 1H), 7.64-7.36 (m, 1H), 6.67 (d, J = 6.3Hz, 1H), 4.40-4.06 (m, 1H), 3.80-3.54 (m, 2H), 2.01-1.64 (m, 3H), 1.26(s, 3H). I-80 377 1.46 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.55(s, 1H), 8.40 (d, J = 6.1 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.68 (d, J= 9.5 Hz, 2H), 6.72 (s, 1H), 4.31 (s, 2H), 4.19-3.63 (m, 2H), 1.77 (d, J= 6.6 Hz, 2H). I-81 424 1.79 1H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J =7.6 Hz, 1H), 8.46-8.16 (m, 2H), 7.90 (d, J = 9.9 Hz, 1H), 7.63 (d, J =7.7 Hz, 2H), 7.33 (dt, J = 40.4, 7.4 Hz, 2H), 6.76 (d, J = 6.3 Hz, 1H),5.06 (s, 1H), 3.44 (d, J = 13.4 Hz, 1H), 3.15 (t, J = 12.2 Hz, 1H), 2.16(td, J = 12.6, 4.1 Hz, 1H), 1.84 (d, J = 13.1 Hz, 1H), 1.65 (d, J = 12.9Hz, 1H). I-82 442 1.9 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.38(s, 1H), 8.26 (d, J = 6.3 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.49 (d, J= 9.2 Hz, 1H), 6.69 (d, J = 6.4 Hz, 1H), 4.73 (s, 1H), 2.96 (d, J = 12.9Hz, 1H), 2.84 (t, J = 13.5 Hz, 1H), 2.61 (d, J = 9.3 Hz, 1H), 2.43 (t, J= 9.9 Hz, 1H), 2.36-2.15 (m, 2H), 1.87 (d, J = 12.6 Hz, 1H), 1.72 (dt, J= 24.0, 11.6 Hz, 3H), 1.55 (q, J = 13.0, 12.2 Hz, 2H). I-83 438 1.7 1HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.44-8.21 (m, 2H), 7.87 (d, J =9.9 Hz, 1H), 7.44-7.13 (m, 5H), 6.79 (d, J = 6.1 Hz, 1H), 4.46 (s, 1H),4.17 (s, 1H), 3.90 (s, 1H), 3.65 (s, 1H), 2.14 (s, 1H), 1.75 (s, 2H).I-84 388 2.2 1H NMR (400 MHz, DMSO-d6) δ 10.16 (m, 1H), 8.47 (s, 1H),8.25 (d, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 7.31 (m, 4H), 7.24 (m, 1H),6.5 (m, 1H), 4.07 (m, 1H), 2.22 (m, 1H), 1.25 (m, 1H), 1.0 (m, 1H).Several peaks overlap with solvent peak. I-85 438 1.95 1H NMR (400 MHz,DMSO-d6) δ 10.20 (d, J = 7.5 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 6.2 Hz,1H), 7.91 (d, J = 9.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.27 (t, J =7.6 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.80 (s, 1H), 4.69 (s, 1H), 3.78(d, J = 13.5 Hz, 2H), 3.51 (s, 3H), 2.07 (s, 2H), 1.70 (s, 1H). I-86 4521.0 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.12 (d, J = 7.5 Hz,1H), 8.48-8.22 (m, 4H), 7.89 (d, J = 9.9 Hz, 1H), 7.65-7.44 (m, 2H),6.85 (d, J = 6.3 Hz, 1H), 3.12 (t, J = 12.5 Hz, 1H), 2.66 (d, J = 5.6Hz, 1H), 2.06 (d, J = 12.3 Hz, 1H), 1.84 (t, J = 12.4 Hz, 2H), 1.53 (t,J = 12.4 Hz, 1H). I-87 329.1 0.80 (500 MHz, Methanol-d4) δ 10.17-10.04(m, 1H), 8.44 (s, 1H), 8.28 (d, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 6.69(d, 1H), 4.43 (s, 1H), 4.31 (s, 1H), 3.18 (t, 1H), 3.04-2.92 (m, 1H),2.92-2.81 (m, 1H), 2.16-2.02 (m, 1H), 1.95-1.84 (m, 1H), 1.64 (q, 1H),1.59-1.40 (m, 1H). I-88 411.1 1.49 (400 MHz, DMSO-d6) δ 10.11 (d, 1H),8.66-8.55 (m, 1H), 8.46-8.33 (m, 2H), 7.95-7.80 (m, 2H), 7.56 (d, 1H),7.38 (dd, 1H), 6.83 (d, 1H), 4.74 (s, 1H), 4.66 (dd, 1H), 4.35 (s, 1H),4.26-4.13 (m, 1H), 3.81 (td, 1H), 3.28-3.16 (m, 1H), 3.16-3.06 (m, 1H).I-89 446.2 1.46 ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.60 (s, 1H),8.44 (d, J = 6.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.68 (dd, J = 9.4,2.0 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 5.09 (dd, J = 11.0, 2.8 Hz, 1H),4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s, 1H), 2.92-2.81 (m, 1H), 2.41 (s,3H), 1.28 (d, J = 6.2 Hz, 3H). I-90 446.2 1.46 ¹H NMR (400 MHz, DMSO-d₆)δ 10.37 (s, 1H), 8.60 (s, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.96 (d, J =9.4 Hz, 1H), 7.68 (dd, J = 9.4, 2.0 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H),5.09 (dd, J = 11.0, 2.8 Hz, 1H), 4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s,1H), 2.92-2.81 (m, 1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H). I-91403.2 1.24 ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (d, J = 1.4 Hz, 1H), 8.61(s, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.92 (dd, J = 9.3, 1.0 Hz, 1H), 7.70(dd, J = 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 5.07 (dd, J = 11.0,2.8 Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J = 10.9, 6.3, 2.7 Hz, 1H),2.91-2.80 (m, 1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H). I-92 403.21.26 1H NMR (400 MHz, DMSO-d₆) δ 10.40 (d, J = 1.4 Hz, 1H), 8.61 (s,1H), 8.44 (d, J = 6.2 Hz, 1H), 7.92 (dd, J = 9.3, 1.0 Hz, 1H), 7.70 (dd,J = 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 5.07 (dd, J = 11.0, 2.8Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J = 10.9, 6.3, 2.7 Hz, 1H), 2.91-2.80(m, 1H), 2.41 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H). I-93 446.3 1.28 ¹H NMR(400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.58 (s, 1H), 8.42 (d, J = 6.1 Hz,1H), 7.95 (d, J = 9.4 Hz, 1H), 7.67 (dd, J = 9.4, 1.9 Hz, 1H), 6.89 (d,J = 6.3 Hz, 1H), 5.01 (dd, J = 11.1, 2.7 Hz, 1H), 4.61 (d, J = 103.5 Hz,2H), 4.07-3.83 (m, 1H), 2.85 (dd, J = 13.2, 10.8 Hz, 1H), 1.26 (d, J =6.2 Hz, 3H). I-94 403.2 1.07 ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H),8.61 (s, 1H), 8.44 (d, J = 6.3 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.70(dd, J = 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 4.99 (dd, J = 11.1,2.7 Hz, 1H), 4.66 (d, J = 106.3 Hz, 2H), 3.98-3.83 (m, 1H), 2.94-2.76(m, 1H), 1.27 (d, J = 6.2 Hz, 3H). I-95 412.2 1.11 ¹H NMR (400 MHz,DMSO-d₆) δ 10.00 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.44-8.37 (m, 1H),7.79 (dd, J = 9.6, 2.2 Hz, 1H), 7.49 (dd, J = 9.5, 2.5 Hz, 1H),6.90-6.83 (m, 1H), 4.99 (dd, J = 11.1, 2.7 Hz, 1H), 4.78 (s, 1H), 4.48(s, 1H), 3.90 (t, J = 8.4 Hz, 1H), 2.84 (t, J = 12.0 Hz, 1H), 2.53 (d, J= 23.2 Hz, 3H), 1.26 (d, J = 5.9 Hz, 3H). I-96 384.1 1.29 ¹H NMR (400MHz, DMSO-d₆) δ 9.98 (d, J = 2.6 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.36(dd, J = 6.4, 2.2 Hz, 1H), 7.78 (dd, J = 9.5, 2.2 Hz, 1H), 7.57-7.43 (m,1H), 6.79 (dd, J = 6.5, 2.1 Hz, 1H), 4.48 (d, J = 40.8 Hz, 2H),4.33-4.07 (m, 4H), 3.60 (d, J = 7.8 Hz, 1H), 3.10 (t, J = 12.3 Hz, 1H),2.92 (dt, J = 37.3, 12.3 Hz, 2H), 2.20 (d, J = 14.0 Hz, 1H), 1.82 (q, J= 11.5 Hz, 1H). I-97 370.1 0.82 ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s,1H), 8.51 (d, J = 2.9 Hz, 1H), 8.43-8.31 (m, 1H), 7.81 (d, J = 9.6 Hz,1H), 7.52 (d, J = 9.6 Hz, 1H), 6.83 (d, J = 6.3 Hz, 1H), 6.59 (s, 1H),4.55 (d, J = 55.4 Hz, 2H), 3.71 (d, J = 11.1 Hz, 2H), 3.47 (t, J = 9.0Hz, 1H), 3.15-2.79 (m, 4H). I-98 385.1 1.35 ¹H NMR (400 MHz, DMSO-d₆) δ10.00 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.35 (dd, J = 6.3, 2.2 Hz, 1H),7.80 (dd, J = 9.7, 2.3 Hz, 1H), 7.52 (d, J = 9.3 Hz, 1H), 7.34-6.97 (m,2H), 6.80 (d, J = 6.4 Hz, 1H), 6.44 (s, 1H), 4.46 (d, J = 44.9 Hz, 2H),4.26-4.12 (m, 1H), 3.22-2.90 (m, 4H), 2.77 (dt, J = 23.4, 12.1 Hz, 2H),2.05 (d, J = 12.3 Hz, 1H), 1.69 (d, J = 11.9 Hz, 1H). I-99 371.1 0.91 ¹HNMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.54 (d, J = 1.7 Hz, 1H),8.48-8.37 (m, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 9.8 Hz, 1H),6.85 (d, J = 6.3 Hz, 1H), 4.79 (s, 1H), 4.56 (s, 1H), 4.48 (t, J = 8.6Hz, 1H), 4.12-4.05 (m, 1H), 3.96 (dd, J = 11.5, 8.3 Hz, 1H), 3.71 (d, J= 11.3 Hz, 1H), 3.05 (dt, J = 40.0, 12.6 Hz, 3H). I-100 380.2 0.97 ¹HNMR (400 MHz, DMSO-d₆) δ 12.65 (s, 1H), 10.03 (d, J = 2.1 Hz, 1H), 8.44(d, J = 1.8 Hz, 1H), 8.33 (dd, J = 6.3, 1.9 Hz, 1H), 7.80 (dd, J = 9.7,1.8 Hz, 1H), 7.74-7.39 (m, 3H), 6.84 (dd, J = 6.4, 1.9 Hz, 1H), 4.53 (s,2H), 3.18-2.98 (m, 2H), 2.76 (t, J = 10.9 Hz, 1H), 2.10 (d, J = 12.4 Hz,1H), 1.84 (d, J = 13.0 Hz, 1H), 1.77-1.50 (m, 2H). I-101 414.2 1.05 ¹HNMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.31(dd, J = 6.4, 1.8 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 9.4Hz, 1H), 7.56 (s, 2H), 6.84 (d, J = 6.3 Hz, 1H), 4.45 (s, 2H), 3.09 (q,J = 11.9 Hz, 3H), 2.85-2.60 (m, 1H), 2.12-1.96 (m, 1H), 1.81 (d, J =12.7 Hz, 1H), 1.65 (tq, J = 24.5, 12.3, 11.5 Hz, 2H), 1.20 (t, J = 7.4Hz, 1H). I-102 357.1 1.1 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.43(d, J = 2.2 Hz, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H),7.50 (d, J = 9.6 Hz, 1H), 7.41 (s, 1H), 6.91 (s, 1H), 6.80 (d, J = 6.4Hz, 1H), 4.42 (s, 2H), 3.09 (dt, J = 32.0, 12.4 Hz, 2H), 2.37 (s, 1H),1.93 (d, J = 13.4 Hz, 1H), 1.74 (dt, J = 24.2, 13.3 Hz, 2H), 1.48 (t, J= 13.1 Hz, 1H). I-114 441 1.1 1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1H),10.41 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H),7.71 (s, 1H), 7.47 (s, 1H), 6.87 (s, 1H), 2.73 (d, J = 50.4 Hz, 4H),2.16 (d, J = 31.7 Hz, 3H), 1.98 (s, 1H), 1.75 (s, 1H), 1.43 (s, 1H),1.26 (s, 1H), 1.02 (d, J = 6.3 Hz, 3H). I-115 443 1.2 1H NMR (300 MHz,DMSO-d6) δ 12.49 (d, J = 28.6 Hz, 1H), 10.36 (s, 1H), 8.73 (s, 1H), 8.44(d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H),7.60-7.16 (m, 2H), 4.55 (d, J = 10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t,1H), 2.78 (t, 1H), 2.37-2.05 (m, 3H), 1.23 (d, J = 6.1 Hz, 3H).1.2 min,443). I-116 443 1.2 1H NMR (300 MHz, DMSO-d6) δ 12.49 (d, J = 28.6 Hz,1H), 10.36 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.96 (d, J =9.4 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.60-7.16 (m, 2H), 4.55 (d, J =10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t, 1H), 2.78 (t, 1H), 2.37-2.05 (m,3H), 1.23 (d, J = 6.1 Hz, 3H).1.2 min, 443). I-117 429 1.4 1H NMR (300MHz, DMSO-d6) δ 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J =5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H),7.55 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H), 4.57 (dd, J = 25.6, 12.1 Hz,3H), 3.79 (d, J = 7.2 Hz, 1H), 3.06 (t, J = 12.3 Hz, 1H), 2.79 (t, J =11.8 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H). I-118 429 1.4 1H NMR (300 MHz,DMSO-d6) δ 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J = 5.3Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H), 7.55(s, 1H), 7.33 (d, J = 5.3 Hz, 1H), 4.57 (dd, J = 25.6, 12.1 Hz, 3H),3.79 (d, J = 7.2 Hz, 1H), 3.06 (t, J = 12.3 Hz, 1H), 2.79 (t, J = 11.8Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H). I-119 443 1.1 1H NMR (300 MHz,DMSO-d6) δ 12.52 (s, 1H), 10.38 (s, 1H), 8.56 (s, 1H), 8.38 (d, J = 6.2Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.76-7.49 (m, 2H), 6.89 (d, J = 6.3Hz, 1H), 4.63-4.22 (m, 3H), 3.79 (s, 1H), 3.10 (t, J = 12.0 Hz, 1H),2.84-2.69 (m, 1H), 2.25 (s, 3H), 1.25 (d, J = 6.2 Hz, 3H). I-120 443 1.11H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.38 (s, 1H), 8.56 (s, 1H),8.38 (d, J = 6.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.76-7.49 (m, 2H),6.89 (d, J = 6.3 Hz, 1H), 4.63-4.22 (m, 3H), 3.79 (s, 1H), 3.10 (t, J =12.0 Hz, 1H), 2.84-2.69 (m, 1H), 2.25 (s, 3H), 1.25 (d, J = 6.2 Hz, 3H).I-123 452.90 1.825 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H), 8.53 (s,1H), 8.33 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.72-7.62 (m,1H), 6.75 (d, J = 6.4 Hz, 1H), 3.03 (d, J = 11.1 Hz, 6H), 2.34-2.26 (m,1H), 2.01-1.82 (m, 2H), 1.28-1.08 (m, 2H), 0.96 (d, J = 6.6 Hz, 3H).I-126 430.1 1.47 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 10.37 (s, 1H),8.73 (s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79(s, 1H), 7.74-7.65 (m, 1H), 7.55 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H), 4.57(dd, J = 25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz, 1H), 3.06 (t, J = 12.3Hz, 1H), 2.79 (t, J = 11.8 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H). I-127430.1 1.47 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s,1H), 8.45 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.79 (s, 1H),7.74-7.65 (m, 1H), 7.55 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H), 4.57 (dd, J =25.6, 12.1 Hz, 3H), 3.79 (d, J = 7.2 Hz, 1H), 3.06 (t, J = 12.3 Hz, 1H),2.79 (t, J = 11.8 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H). I-136 407.1 1.59(300 MHz, DMSO, ppm): 12.65 (s, 1H), 10.35 (s, 1H), 8.70 (s, 1H), 8.40(d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.82-7.67 (m, 1H), 7.61(s, 1H), 7.43 (s, 1H), 7.23 (d, J = 5.3 Hz, 1H), 4.86 (d, J = 10.2 Hz,1H), 4.68 (d, J = 12.8 Hz, 1H), 2.72 (d, J = 9.4 Hz, 2H), 2.59 (d, J =12.0 Hz, 1H), 2.15-1.90 (m, 1H), 1.71 (s, 1H), 1.31 (q, J = 12.0 Hz,1H), 0.98 (d, J = 6.5 Hz, 3H). I-137 407.1 1.46 (300 MHz, DMSO, ppm):12.64 (s, 1H), 10.36 (s, 1H), 8.70 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H),7.96 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 9.4, 1.9 Hz, 1H), 7.61 (s, 1H),7.43 (s, 1H), 7.24 (d, J = 5.4 Hz, 1H), 4.86 (d, J = 9.1 Hz, 1H), 4.69(d, J = 12.7 Hz, 1H), 2.73 (d, J = 9.4 Hz, 2H), 2.59 (d, J = 12.1 Hz,1H), 2.06 (d, J = 12.9 Hz, 1H), 1.73 (s, 1H), 1.31 (q, J = 11.9 Hz, 1H),0.99 (d, J = 6.5 Hz, 3H). I-149 405.2 1.38 1H NMR (400 MHz, DMSO-d6) δ10.39 (d, J = 15.2 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.31 (ddd, J =15.4, 6.3, 2.1 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.84-7.54 (m, 1H),7.40 (s, 1H), 7.03-6.73 (m, 2H), 3.78-3.50 (m, 2H), 2.93 (m, 1H),2.45-2.0 (m, 2H), 1.58-1.35 (m, 2H), 1.02-0.74 (m, 3H). I-154 391.2 1.311H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.53 (s, 1H), 8.34 (dd, J =6.3, 2.3 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.68 (d, J = 9.5 Hz, 1H),7.40 (s, 1H), 7.00-6.74 (m, 2H), 4.50 (m, 2H), 3.11 (dt, J = 35.7, 12.4Hz, 2H), 2.42-2.25 (m, 2H), 1.94 (d, J = 12.9 Hz, 1H), 1.76 (dd, J =24.5, 13.2 Hz, 2H), 1.48 (d, J = 12.7 Hz, 1H). I-202 427.1 1.76 1H NMR(400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.59 (s, 1H), 8.44 (d, J = 6.2 Hz,1H), 7.97 (d, J = 9.4 Hz, 1H), 7.73-7.61 (m, 2H), 7.15 (s, 1H), 7.01 (d,J = 6.3 Hz, 1H), 2.75-2.64 (m, 3H). I-214 444.1 1.67 (400 MHz, DMSO-d6)δ 12.48 (d, J = 37.9 Hz, 1H), 10.38 (s, 1H), 8.55 (s, 1H), 8.38 (d, J =6.2 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H),7.45 (s, 1H), 6.87 (d, J = 6.3 Hz, 1H), 4.55 (dd, J = 11.0, 2.7 Hz, 1H),4.49-4.19 (m, 2H), 3.85-3.67 (m, 1H), 3.09 (t, J = 12.1 Hz, 1H),2.85-2.69 (m, 1H), 2.25 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H). I-247 396.01.11 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 9.94 (s, 1H), 8.73-8.54 (m,1H), 8.40 (d, J = 3.8 Hz, 1H), 7.91-7.70 (m, 2H), 7.53 (d, J = 10.5 Hz,2H), 7.26 (d, J = 4.9 Hz, 1H), 4.57 (d, J = 32.9 Hz, 3H), 3.80 (d, J =10.8 Hz, 1H), 3.17-2.63 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H). I-248 396.01.10 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 9.96 (s, 1H), 8.62 (s, 1H),8.42 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 10.6 Hz, 2H), 7.28(s, 1H), 4.63 (d, J = 11.5 Hz, 3H), 3.81 (s, 1H), 3.23-2.68 (m, 2H),1.26 (d, J = 6.0 Hz, 3H). I-249 400.1 1.71 (300 MHz, DMSO, ppm): 12.64(s, 1H), 9.62 (s, 1H), 8.46 (s, 1H), 8.32 (d, J = 5.3 Hz, 1H), 7.87-7.36(m, 3H), 7.14 (t, J = 7.2 Hz, 2H), 4.80 (dd, J = 37.2, 11.9 Hz, 2H),3.45 (qd, J = 7.0, 5.1 Hz, 1H), 2.89-2.66 (m, 2H), 2.03 (d, J = 12.7 Hz,1H), 1.71 (s, 2H), 1.26 (dd, J = 20.9, 8.9 Hz, 1H), 1.09-0.85 (m, 5H),0.64 (s, 2H). I-259 451.1 2.11 1H NMR (400 MHz, DMSO-d6, ppm) 12.66 (s,1H), 9.05 (s, 1H), 8.44 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 7.69 (d, J =9.5 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.15 (d, J = 5.3 Hz, 1H), 7.04(d, J = 9.5 Hz, 1H), 4.80-4.77 (m, 2H), 4.14-3.71 (m, 4H), 2.87-2.83 (m,1H), 2.78-2.73 (m, 1H), 2.59-2.55 (m, 1H), 2.00-1.98 (m, 1H), 1.72-1.70(m, 1H), 1.34-1.30 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H). I-261 451.2 1.191H NMR (300 MHz, DMSO-d6, ppm) 12.53 (s, 1H), 9.10 (s, 1H), 8.43 (s,1H), 8.31 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.53 (s, 1H),7.39 (s, 1H), 7.12 (d, J = 5.3 Hz, 1H), 7.08-7.04 (m, 1H), 4.32-4.08 (m,4H), 4.02-3.90 (m, 3H), 3.59-3.56 (m, 1H), 3.15-3.10 (m, 1H), 1.94-1.90(m, 2H), 1.72-1.62 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H). I-271 415.0 1.151H NMR (300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86 (s, 1H), 8.37 (s,1H), 8.28 (d, J = 5.3 Hz, 1H), 7.57 (d, J = 9.5 Hz, 3H), 7.10 (d, J =5.3 Hz, 1H), 6.88 (dd, J = 9.5, 2.1 Hz, 1H), 4.76 (d, J = 11.7 Hz, 2H),3.56 (br s, 4H), 2.76 (t, J = 12.7 Hz, 2H), 2.44 (s, 1H), 2.12 (s, 2H),1.95 (d, J = 12.7 Hz, 1H), 1.67 (s, 1H), 1.26 (q, J = 11.7 Hz, 1H), 0.94(d, J = 6.5 Hz, 3H). I-287 465.1 1.24 1H NMR (400 MHz, DMSO-d6, ppm)12.55 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 7.68 (d, J = 9.5 Hz, 1H),7.56 (s, 1H), 7.40 (s, 1H), 7.10-7.01 (m, 2H), 4.14 (s, 4H), 4.02 (s,1H), 3.98 (d, J = 12.8 Hz, 2H), 3.52 (s, 1H), 3.11 (s, 1H), 2.32 (s,3H), 1.89 (d, J = 9.3 Hz, 2H), 1.67 (s, 1H), 0.97 (d, J = 6.5 Hz, 3H).I-288 465.1 1.23 (400 MHz, DMSO-d6. ppm) 12.67 (s, 1H), 9.06 (s, 1H),8.39 (s, 1H), 7.67 (d, J = 9.6 Hz, 2H), 7.45 (s, 1H), 7.08 (s, 1H), 7.02(d, J = 9.5 Hz, 1H), 4.82 (d, J = 10.4 Hz, 2H), 4.07 (s, 4H), 2.77 (d, J= 11.5 Hz, 2H), 2.55 (d, J = 17.2 Hz, 1H), 2.32 (s, 3H), 1.98 (d, J =12.7 Hz, 1H), 1.71 (s, 1H), 1.28 (q, J = 12.1 Hz, 1H), 0.98 (d, J = 6.5Hz, 3H). I-272 415.0 1.16 (300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86(s, 1H), 8.37 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 7.65-7.33 (m, 3H), 7.10(d, J = 5.3 Hz, 1H), 6.88 (dd, J = 9.5, 2.1 Hz, 1H), 4.85-4.72 (m, 2H),3.72-3.35 (m, 4H), 2.87-2.73 (m, 2H), 2.57-2.43 (m, 1H), 2.20-2.03 (m,2H), 2.01-1.90 (m, 1H), 1.80-1.63 (m, 1H), 1.32-1.09 (m, 1H), 0.94 (d, J= 6.5 Hz, 3H). I-310 429 1.392 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31(1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6.84 (1H), 3.82 (1H), 2.83 (2H),2.58 (2H), 2.42 (1H), 1.13 (3H) I-312 463.1 1.08 1H NMR (400 MHz,DMSO-d6) d 10.50 (dd, J = 1.9, 0.9 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J =6.3 Hz, 1H), 7.95 (dd, J = 9.4, 0.9 Hz, 1H), 7.81 (dd, J = 9.4, 1.9 Hz,1H), 6.73 (d, J = 6.4 Hz, 1H), 5.14-3.91 (m, 3H), 3.37 (s, 3H), 3.22(td, J = 10.4, 9.8, 5.1 Hz, 1H), 3.06 (d, J = 0.9 Hz, 3H), 3.02 (d, J =0.9 Hz, 3H), 2.55 (s, 1H), 1.93 (d, J = 12.8 Hz, 1H), 1.76-1.58 (m, 1H),1.17 (q, J = 11.9 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H). I-313 424.2 1.19 1HNMR (400 MHz, DMSO-d6) d 12.61 (s, 1H), 10.54 (dd, J = 2.0, 0.9 Hz, 1H),8.54 (s, 1H), 8.34 (d, J = 6.3 Hz, 1H), 7.95 (dd, J = 9.4, 0.9 Hz, 1H),7.81 (dd, J = 9.4, 1.9 Hz, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 6.87 (d, J =6.3 Hz, 1H), 4.49 (d, J = 54.0 Hz, 4H), 3.11 (d, J = 23.8 Hz, 2H), 2.71(d, J = 24.5 Hz, 2H), 2.16-2.03 (m, 1H), 1.85 (d, J = 5.6 Hz, 1H),1.79-1.55 (m, 2H). I-314 444.0 0.93 (300 MHz, DMSO, ppm) 12.34 (d, J =35.0 Hz, 1H), 10.35 (s, 1H), 8.48 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H),7.92 (d, J = 9.4 Hz, 1H), 7.65 (m, 1H), 7.36 (s, 1H), 6.79 (d, J = 6.4Hz, 1H), 5.12 (d, J = 4.6 Hz, 1H), 4.46 (s, 1H), 3.31 (m, 1H), 3.56 (d,J = 4.9 Hz, 1H), 2.67 (d, J = 26.7 Hz, 3H), 2.16 (s, 4H), 1.60 (s, 1H).I-315 444.0 0.93 (300 MHz, DMSO, ppm) 12.33 (d, J = 36.2 Hz, 1H), 10.35(s, 1H), 8.48 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.92 (d, J = 9.4 Hz,1H), 7.78-7.25 (m, 2H), 6.79 (d, J = 6.4 Hz, 1H), 5.12 (d, J = 4.5 Hz,1H), 4.82-4.01 (s, 1H), 3.56 (s, 1H), 3.31 (m, 1H), 2.87-2.54 (m, 3H),2.17 (m, 4H), 1.59 (s, 1H). I-318 465.5 1.29 1H NMR (400 MHz, DMSO-d6) d12.61 (s, 1H), 10.50 (dd, J = 2.0, 0.9 Hz, 1H), 8.52 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 8.17 (s, 1H), 7.94 (dd, J = 9.4, 0.8 Hz, 1H), 7.64 (dd, J= 9.4, 1.9 Hz, 2H), 7.53 (s, 1H), 6.86 (d, J = 6.3 Hz, 1H), 4.47 (d, J =66.6 Hz, 2H), 3.20-3.04 (m, 2H), 2.75 (dd, J = 9.7, 5.1 Hz, 1H), 2.21(dt, J = 6.7, 3.4 Hz, 1H), 2.09 (dd, J = 11.2, 3.5 Hz, 1H), 1.89-1.78(m, 1H), 1.79-1.67 (m, 1H), 1.67-1.56 (m, 1H), 0.60-0.45 (m, 2H), 0.41(qd, J = 5.4, 2.4 Hz, 2H). I-319 504.2 1.23 1H NMR (400 MHz, DMSO-d6) d10.46 (dd, J = 2.0, 0.9 Hz, 1H), 8.52 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H),8.19 (s, 1H), 7.94 (dd, J = 9.5, 0.9 Hz, 1H), 7.65 (dd, J = 9.4, 1.9 Hz,1H), 6.73 (d, J = 6.4 Hz, 1H), 4.94-4.07 (m, 3H), 3.23 (s, 1H), 3.05(dd, J = 13.6, 0.9 Hz, 6H), 2.70-2.59 (m, 1H), 2.26 (dt, J = 6.8, 3.4Hz, 1H), 1.94 (d, J = 12.8 Hz, 1H), 1.75-1.57 (m, 1H), 1.17 (q, J = 12.0Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.60-0.46 (m, 2H), 0.47-0.34 (m, 2H).I-320 425.1 1.09 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.49 (dd, J= 1.9, 0.9 Hz, 1H), 8.51 (s, 1H), 8.32 (d, J = 6.3 Hz, 1H), 7.93 (dd, J= 9.4, 0.9 Hz, 1H), 7.72 (dd, J = 9.4, 1.9 Hz, 1H), 7.70-7.41 (m, 4H),6.86 (d, J = 6.4 Hz, 1H), 4.48 (d, J = 59.9 Hz, 2H), 3.11 (tt, J = 10.6,4.5 Hz, 2H), 2.73 (dd, J = 9.1, 5.0 Hz, 1H), 2.14-2.05 (m, 1H), 1.83 (d,J = 13.4 Hz, 1H), 1.70 (ddd, J = 22.7, 11.5, 2.9 Hz, 1H), 1.65-1.55 (m,1H). I-322 485 2.037 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80(2H), 7.57 (1H), 7.46 (1H), 6.84 (1H), 4.72 (1H), 4.47 (4H), 3.82 (1H),2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H) I-325 477.25 1.392 ¹H NMR(400 MHz, Chloroform-d) δ 9.90 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.24(d, J = 6.2 Hz, 1H), 7.73 (d, J = 9.7 Hz, 1H), 7.40-7.34 (m, 2H),7.23-7.09 (m, 2H), 7.09-7.01 (m, 2H), 6.41 (d, J = 6.2 Hz, 1H), 4.51 (s,2H), 3.29 (dq, J = 10.5, 5.3, 4.4 Hz, 1H), 3.05 (d, J = 13.3 Hz, 7H),2.73 (t, J = 11.9 Hz, 1H), 2.47 (t, J = 12.4 Hz, 1H), 2.07 (d, J = 13.1Hz, 1H), 1.31 (q, J = 12.0 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H). I-328464.2 1.00 1H NMR (400 MHz, DMSO-d6) δ 10.45 (dd, J = 2.0, 0.9 Hz, 1H),8.51 (s, 1H), 8.31 (d, J = 6.3 Hz, 1H), 7.92 (dd, J = 9.4, 0.9 Hz, 1H),7.72 (dd, J = 9.4, 1.9 Hz, 1H), 7.63 (s, 2H), 6.73 (d, J = 6.4 Hz, 1H),4.51 (s, 3H), 3.29-3.16 (m, 1H), 3.06 (d, J = 0.9 Hz, 3H), 3.03 (d, J =0.9 Hz, 3H), 2.68-2.56 (m, 1H), 1.93 (d, J = 12.6 Hz, 1H), 1.76-1.59 (m,1H), 1.17 (q, J = 11.9 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H). I-329 437.901.857 1H NMR (400 MHz, Chloroform-d) d 9.88 (dd, J = 2.4, 0.8 Hz, 1H),8.56 (s, 1H), 8.26 (d, J = 6.2 Hz, 1H), 7.74 (dd, J = 9.7, 0.8 Hz, 1H),7.50 (s, 2H), 7.41-7.33 (m, 2H), 7.20 (dd, J = 9.6, 2.3 Hz, 1H),7.18-7.12 (m, 1H), 7.09-7.04 (m, 2H), 6.40 (d, J = 6.2 Hz, 1H), 4.25 (s,1H), 3.20-2.93 (m, 2H), 1.91-1.79 (m, 2H), 1.78-1.63 (m, 2H), 1.60-1.40(m, 2H). Spectra I-330 458.2 1.16 ¹H NMR (400 MHz, DMSO-d6) δ 9.11 (s,1H), 8.41 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H),7.13 (d, J = 5.3 Hz, 1H), 7.03 (dd, J = 9.5, 2.1 Hz, 1H), 5.55 (d, J =57.5 Hz, 1H), 4.70 (d, J = 12.6 Hz, 2H), 4.26 (d, J = 6.7 Hz, 2H), 4.03(ddd, J = 34.5, 23.2, 9.1 Hz, 2H), 3.01 (d, J = 6.1 Hz, 7H), 2.65 (d, J= 14.6 Hz, 1H), 1.99 (d, J = 12.7 Hz, 1H), 1.68 (s, 1H), 1.13 (q, J =11.9 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H). I-340 434.90 1.546 ¹H NMR (400MHz, Chloroform-d) δ 10.22 (dd, J = 2.5, 1.5 Hz, 1H), 8.59 (s, 1H), 8.29(d, J = 6.3 Hz, 1H), 7.85-7.75 (m, 1H), 7.45 (dd, J = 9.3, 1.8 Hz, 1H),6.45 (d, J = 6.3 Hz, 1H), 3.33 (tt, J = 10.9, 4.4 Hz, 1H), 3.10 (d, J =0.9 Hz, 3H), 3.07 (d, J = 0.9 Hz, 3H), 2.76 (t, J = 13.0, 10.7 Hz, 1H),2.53 (t, J = 12.3 Hz, 1H), 2.09 (ddt, J = 12.7, 4.0, 2.1 Hz, 1H), 1.79(d, J = 12.8 Hz, 3H), 1.42-1.28 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H). I-352489 0.979 12.7 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 7.90 (2H), 7.42(1H), 6.84 (1H), 4.42 (1H), 4.25 (1H), 3.52 (1H), 3.43 (1H), 3.11 (1H),2.32 (1H), 1.83 (1H) I-353 496 1.255 12.84 (1H), 10.36 (1H), 8.56 (1H),8.36 (1H), 8.27 (1H), 7.90 (2H), 7.71 (1H), 7.63 (1H), 7.01 (1H), 6.84(1H), 4.27 (2H), 3.72 (2H), 3.43 (2H), 2.98 (2H), 2.30 (1H) I-362 4851.671 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57(1H), 7.46 (1H), 6.84 (1H), 4.72 (1H), 4.47 (4H), 3.82 (1H), 2.83 (2H),2.58 (2H), 2.42 (1H), 1.13 (3H) I-369 469 1.059 12.70 (1H), 10.06 (1H),8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6.84 (1H), 4.32(2H), 3.39 (2H), 3.22 (2H), 2.39 (2H), 1.95 (1H), 0.85 (1H), 0.45 (2H),0.04 (2H) I-380 406.1 1.0 1H NMR (400 MHz, DMSO-d6) δ 10.42 (d, J = 38.1Hz, 1H), 8.53 (s, 1H), 8.38 (dd, J = 15.5, 6.2 Hz, 1H), 7.95 (d, J = 9.4Hz, 1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H), 7.27 (d, J = 43.5 Hz, 2H), 6.76(d, J = 6.3 Hz, 1H), 3.08 (d, J = 12.7 Hz, 2H), 2.88-2.62 (m, 1H), 1.12(d, J = 6.7 Hz, 3H). I-398 437.95 1.398 1H NMR (400 MHz, Chloroform-d) d9.87 (s, 1H), 8.54 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 38.3Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.15 (q, J = 9.0, 7.5 Hz, 2H), 7.05(d, J = 8.0 Hz, 2H), 6.87 (s, 1H), 6.43 (d, J = 6.2 Hz, 1H), 4.49 (d, J= 12.8 Hz, 1H), 4.22 (s, 1H), 3.28 (t, J = 11.6 Hz, 1H), 3.11 (t, J =12.2 Hz, 1H), 2.95 (s, 1H), 2.20 (d, J = 12.8 Hz, 1H), 1.95-1.78 (m,2H), 1.65 (d, J = 12.4 Hz, 1H). Spectra I-399 437.95 1.419 1H NMR (400MHz, DMSO-d6) d 9.77-9.66 (m, 1H), 8.42 (d, J = 21.7 Hz, 1H), 8.24 (dd,J = 12.9, 6.3 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.54 (d, J = 5.2 Hz,1H), 7.47-7.29 (m, 2H), 7.21-7.13 (m, 2H), 7.13-7.07 (m, 2H), 6.91 (s,1H), 6.82-6.65 (m, 1H), 4.35 (d, J = 73.8 Hz, 2H), 3.01 (dt, J = 32.7,12.0 Hz, 2H), 2.83-2.61 (m, 1H), 2.05 (t, J = 10.5 Hz, 1H), 1.72 (q, J =11.7 Hz, 2H), 1.49 (d, J = 12.4 Hz, 1H). Spectra I-461 497 2.101 12.84(1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 8.27 (1H), 7.90 (2H), 7.71 (1H),7.63 (1H), 6.84 (1H), 4.27 (2H), 3.72 (2H), 3.43 (2H), 2.98 (2H), 2.30(1H) I-476 538.85 1.469 1H NMR (400 MHz, Chloroform-d) d 10.40 (s, 1H),8.59 (s, 1H), 8.35 (dd, J = 6.2, 1.5 Hz, 1H), 7.83 (d, J = 9.4 Hz, 1H),7.64 (s, 2H), 7.46 (dd, J = 9.4, 1.9 Hz, 1H), 6.44 (dd, J = 6.3, 1.7 Hz,1H), 4.29 (s, 2H), 3.79 (ddd, J = 20.2, 10.4, 4.4 Hz, 1H), 3.60 (tq, J =21.0, 11.1, 9.7 Hz, 1H), 2.76-2.37 (m, 2H), 2.17 (d, J = 54.3 Hz, 1H),1.84-1.53 (m, 1H), 1.22-0.96 (m, 2H), 0.78 (s, 1H), 0.62 (s, 1H). I-481512.80 1.832 1H NMR (400 MHz, Chloroform-d) d 10.35 (s, 1H), 8.73 (s,1H), 8.35 (s, 1H), 7.90 (d, J = 9.9 Hz, 1H), 7.64-7.47 (m, 3H), 6.42 (s,1H), 4.62 (s, 1H), 4.40 (d, J = 5.5 Hz, 1H), 4.29 (d, J = 22.7 Hz, 3H),3.66 (s, 1H), 3.43 (s, 2H), 2.26 (s, 2H), 1.54 (s, 3H), 1.34 (s, 3H).I-484 411.9 1.38 No NMR was obtained due to the limited amount. I-490547.2 0.085 (300 MHz, DMSO) 12.74 (s, 1H), 10.33 (s, 1H), 8.49 (s, 1H),8.34 (d, J = 6.2 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 9.4 Hz,2H), 7.44 (br, 1H), 6.80 (d, J = 6.4 Hz, 1H), 3.94 (br, 2H), 3.81-3.44(m, 5H), 2.81 (s, 3H), 2.80-2.73 (m, 1H), 2.38-2.16 (m, 3H), 2.05-1.93(m, 1H), 1.83-1.72 (m, 1H). I-495 547.2 1.65 (300 MHz, DMSO) 12.74 (s,1H), 10.32 (s, 1H), 8.49 (s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 7.93 (d, J =9.4 Hz, 1H), 7.65 (d, J = 9.5 Hz, 2H), 7.46 (br, 1H), 6.80 (d, J = 6.2Hz, 1H), 3.93 (br, 2H), 3.71 (br, 2H), 3.63-3.51 (m, 2H), 2.81 (s, 3H),2.80-2.73 (m, 1H), 2.38-2.16 (m, 3H), 2.05-1.93 (m, 1H), 1.83-1.72 (m,1H). I-499 434.90 1.847 ¹H NMR (400 MHz, Chloroform-d) δ 10.28-10.15 (m,1H), 8.37-8.29 (m, 2H), 7.81 (d, J = 9.3 Hz, 1H), 7.49 (dd, J = 9.2, 1.8Hz, 1H), 6.91 (d, J = 5.3 Hz, 1H), 4.92-4.82 (m, 1H), 4.82-4.70 (m, 1H),3.37 (tt, J = 10.9, 4.5 Hz, 1H), 3.18-2.99 (m, 6H), 2.78 (dd, J = 12.8,10.7 Hz, 1H), 2.50 (t, J = 12.2 Hz, 1H), 2.15-2.04 (m, 1H), 1.80 (dq, J= 10.6, 6.9 Hz, 1H), 1.34 (q, J = 12.0 Hz, 1H), 1.04 (d, J = 6.6 Hz,3H). I-508 455.1 0.98 (300 MHz, Chloroform-d, ppm) 10.36 (s, 1H),8.41-8.29 (m, 2H), 7.80 (d, J = 9.4 Hz, 1H), 7.59 (s, 2H), 7.45 (dd, J =9.4, 1.9 Hz, 1H), 6.93 (d, J = 5.3 Hz, 1H), 4.22-4.01 (m, 2H), 4.01-3.74(m, 3H), 3.02 (br, 1H), 2.67 (br, 1H), 1.56 (br, 1H), 0.52-0.18 (m,4H).; I-511 540.90 1.849 ¹H NMIR (400 MHz, Chloroform-d) δ 12.34 (s,1H), 10.39 (s, 1H), 8.65 (d, J = 48.3 Hz, 1H), 8.40 (d, J = 23.0 Hz,1H), 8.04 (dd, J = 51.1, 38.0 Hz, 2H), 7.81-7.49 (m, 1H), 6.54 (s, 1H),4.75 (s, 1H), 4.03-3.11 (m, 5H), 3.03 (s, 1H), 1.97 (s, 7H), 1.27 (s,4H), 0.88 (d, J = 20.3 Hz, 2H), 0.10 (s, 3H). I-537 429 1.416 12.70(1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H),6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H) I-543510.2 1.67 (400 MHz, DMSO-d6): 10.39 (s, 1H), 8.71 (s, 1H), 8.48 (d, J =5.2 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.72 (dd, J = 9.4, 1.9 Hz, 1H),7.29 (d, J = 5.3 Hz, 1H), 7.17 (br, 1H), 5.00 (br, 1H), 4.36 (br, 1H),3.71 (br, 1H), 3.26-3.17 (m, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.95 (s,3H), 2.92-2.81 (m, 1H), 2.67-2.57 (m, 1H), 2.39 (t, J = 11.6 Hz, 1H),1.62 (br, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.70 (q, J = 5.9 Hz, 1H), 0.50(p, J = 4.6, 4.2 Hz, 2H), 0.42-0.31 (m, 1H).;

Purity and retention time of the compounds from this invention weremeasured by HPLC.

HPLC method: analytical reverse phase UPLC-MS was carried out on awaters Acquity UPLC-MS system equipped with a waters BEH 1.7 mm C-18reverse phase column (2.1 mm×50 mm, 1.7 μm). The mobile phases wereacetonitrile and water/acetonitrile (95:5 with 10 mM ammonium formate,pH 9). Run time 5 min

Example 17: GCN2 Enzyme Inhibition Assay

Compounds were screened for their ability to inhibit GCN2 kinaseactivity using a Transcreener® ADP² fluorescence polarization assay thatdetects ADP levels (BellBrook Labs, WI). Assays were carried out in abuffer consisting of 25 mM Tris-HCl (pH 7.5), 50 mM NaCl, 10 mM MgCl₂and 1 mM DTT. Final substrate concentrations were 280 μM ATP and 200 μMpeptidic substrate(H-Gly-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-OH[(RS)₇], Bachem, Switzerland). Assays were carried out at 25° C. in thepresence of a (typical) final concentration of 4 nM GCN2 kinase.

An assay buffer containing GCN2 kinase and (RS)₇ was prepared. 4.7 μL ofthis stock solution was placed per well of a black, low volume, 384-wellmicrotitre plate (e.g. catalogue number 3676, Corning Inc., NY). To thiswas added 0.65 μM of DMSO containing serial dilutions of the testcompound (typical final concentrations of test compound were 0 to 8 μM).The plate was incubated for 10 minutes at 25° C. prior to the additionof 4.7 μL of ATP stock buffer to initiate the enzyme reaction. Thereaction was allowed to proceed for 1 hour at 25° C., prior to theaddition of 10 μL detection buffer (consisting of appropriateconcentrations of ADP² antibody and ADP Alexa633 tracer in 1× stop anddetect buffer as supplied by BellBrook Labs). The reaction was left toincubate for 1 hour at 25° C., prior to measuring the fluorescencepolarisation signal (mP) in each well using a PHERAstar FS reader (BMGLabtech, Germany).

Fluorescence polarization values were normalized to an in plate standardcurve consisting of various ratios of ATP to ADP in assay buffer to afinal total concentration of 280 μM. 9.4 μL of each ATP:ADP ratio bufferwas added to the plate along with 0.65 μL DMSO, prior to addition ofdetection buffer, to mimic assay volumes and conditions. The standardcurve was used to convert mP values obtained from test wells intopercentage ATP converted to ADP. Percentage inhibition of enzymeactivity was then calculated at each compound dose. IC₅₀ and Ki_((app))(using known assay and kinetic parameters) values were calculated frompercentage inhibition data using a non-linear, tight-binding algorithm.All data analysis was undertaken using the Screener® software package(Genedata, Switzerland).

TABLE 3 Enzyme activity for compounds of formula I Compound GCN2 (Ki)I-1 ++ I-2 +++ I-3 +++ I-4 ++ I-5 ++ I-6 ++ I-7 + I-8 ++ I-9 +++ I-10+++ I-11 ++ I-12 +++ I-13 +++ I-14 ++ I-15 +++ I-16 +++ I-17 +++ I-18+++ I-19 ++ I-20 +++ I-21 ++ I-22 +++ I-23 +++ I-24 +++ I-25 +++ I-26 +I-27 +++ I-28 +++ I-29 +++ I-30 + I-31 ++ I-32 ++ I-33 ++ I-34 +++ I-35++ I-36 +++ I-37 +++ I-38 ++ I-39 +++ I-40 +++ I-41 +++ I-42 +++ I-43+++ I-44 +++ I-45 +++ I-46 ++ I-47 +++ I-48 +++ I-49 ++ I-50 +++ I-51+++ I-52 +++ I-53 +++ I-54 ++ I-55 ++ I-56 ++ I-57 ++ I-58 ++ I-59 +I-62 ++ I-63 +++ I-65 ++ I-66 ++ I-76 + I-77 + I-81 ++ I-83 ++ I-84 +I-85 + I-86 ++ I-87 + I-88 + I-89 ++ I-90 +++ I-91 ++ I-92 +++ I-93 ++I-94 + I-95 ++ I-96 +++ I-97 ++ I-98 ++ I-99 ++ I-100 +++ I-101 +++I-102 +++ I-103 +++ I-104 ++ I-105 ++ I-106 ++ I-107 +++ I-108 +++ I-109++ I-110 +++ I-111 ++ I-112 +++ I-113 +++ I-114 +++ I-115 +++ I-116 +++I-117 +++ I-118 +++ I-119 +++ I-120 +++ I-137 +++ I-154 +++ I-137 +++I-149 +++ I-202 +++ I-380 +++ I-484 +++ +++ for Ki < 10 nM; ++ for Ki in10 nM-100 nM range; and + for Ki 100 nM-1 μM.

TABLE 4 Enzyme activity for compounds of formula I Compound GCN2 (IC₅₀)I-122 +++ I-123 ++ I-124 +++ I-125 +++ I-126 +++ I-127 +++ I-128 ++I-129 ++ I-130 ++ I-131 + I-132 ++ I-133 + I-134 ++ I-135 +++ I-136 +++I-137 +++ I-138 ++ I-139 + I-140 + I-141 + I-142 + I-143 ++ I-144 +I-145 + I-146 + I-147 ++ I-148 +++ I-149 +++ I-150 ++ I-151 + I-152 ++I-153 +++ I-154 +++ I-155 + I-156 + I-157 + I-158 ++ I-159 ++ I-160 +++I-161 ++ I-162 ++ I-163 ++ I-164 ++ I-165 ++ I-166 ++ I-167 + I-168 ++I-169 ++ I-170 ++ I-171 ++ I-172 ++ I-173 + I-174 ++ I-175 +++ I-176 +++I-177 ++ I-178 + I-179 +++ I-180 +++ I-181 ++ I-182 ++ I-183 ++ I-184 ++I-185 ++ I-186 +++ I-187 ++ I-188 ++ I-189 ++ I-190 + I-191 ++ I-192 ++I-193 +++ I-195 ++ I-196 +++ I-197 ++ I-198 +++ I-199 +++ I-200 +++I-201 ++ I-202 +++ I-203 ++ I-204 ++ I-205 ++ I-206 ++ I-207 + I-208 ++I-209 ++ I-210 + I-211 + I-212 + I-213 ++ I-214 + I-217 ++ I-218 ++I-219 ++ I-220 ++ I-221 +++ I-222 ++ I-223 +++ I-224 + I-225 + I-226 +I-227 ++ I-228 + I-229 +++ I-230 ++ I-231 + I-232 + I-233 + I-234 ++I-235 ++ I-236 ++ I-238 ++ I-239 + I-240 + I-241 ++ I-242 ++ I-243 +I-244 ++ I-245 ++ I-246 ++ I-247 +++ I-248 +++ I-249 +++ I-250 ++ I-251++ I-252 + I-253 + I-254 + I-255 + I-256 + I-257 + I-258 ++ I-259 +++I-260 +++ I-261 +++ I-262 ++ I-263 ++ I-264 +++ I-265 ++ I-266 +++ I-267++ I-268 +++ I-269 ++ I-270 +++ I-271 ++ I-272 +++ I-273 +++ I-274 ++I-275 +++ I-276 + I-277 ++ I-278 +++ I-279 ++ I-280 ++ I-281 ++ I-282 +I-283 ++ I-284 ++ I-285 + I-286 +++ I-287 ++ I-288 +++ I-289 ++ I-290 ++I-291 ++ I-292 + I-293 +++ I-294 + I-295 ++ I-296 + I-297 ++ I-298 +I-299 + I-300 ++ I-301 + I-302 +++ I-303 ++ I-304 ++ I-305 + I-307 ++I-308 ++ I-309 + I-310 +++ I-311 ++ I-312 + I-313 ++ I-314 +++ I-315 +++I-316 +++ I-317 ++ I-318 + I-319 + I-320 ++ I-321 ++ I-322 ++ I-323 +++I-324 + I-325 + I-326 +++ I-327 ++ I-328 + I-329 ++ I-330 + I-331 +I-332 + I-333 + I-334 + I-335 + I-336 ++ I-337 + I-338 + I-339 ++ I-340+++ I-341 + I-342 ++ I-343 + I-344 + I-345 + I-346 ++ I-347 + I-348 ++I-349 ++ I-350 + I-351 +++ I-352 +++ I-353 +++ I-354 +++ I-355 + I-356++ I-357 ++ I-358 +++ I-359 +++ I-360 +++ I-361 ++ I-362 +++ I-363 +I-364 + I-365 + I-366 +++ I-367 + I-368 + I-369 +++ I-370 +++ I-371 +++I-372 +++ I-373 +++ I-374 +++ I-375 ++ I-376 ++ I-377 ++ I-378 ++ I-379++ I-380 +++ I-382 + I-383 +++ I-384 +++ I-385 +++ I-386 + I-387 +I-388 + I-389 ++ I-390 +++ I-391 + I-392 + I-393 + I-394 + I-395 + I-396++ I-397 ++ I-398 + I-399 ++ I-400 ++ I-401 + I-402 + I-403 + I-404 ++I-405 ++ I-406 ++ I-407 ++ I-408 ++ I-409 ++ I-410 + I-411 + I-412 +I-413 + I-414 ++ I-415 + I-416 ++ I-417 + I-418 ++ I-419 ++ I-420 ++I-421 ++ I-422 ++ I-423 + I-424 ++ I-425 + I-426 ++ I-427 ++ I-428 ++I-429 +++ I-432 ++ I-433 ++ I-434 + I-435 +++ I-436 ++ I-437 + I-438 ++I-439 + I-440 + I-441 ++ I-442 ++ I-443 ++ I-444 ++ I-445 ++ I-446 ++I-447 ++ I-448 ++ I-449 +++ I-450 ++ I-451 ++ I-452 + I-454 ++ I-455 ++I-456 ++ I-457 ++ I-458 ++ I-459 +++ I-460 ++ I-461 +++ I-462 + I-463 ++I-464 + I-465 + I-466 ++ I-467 ++ I-468 + I-469 ++ I-470 +++ I-471 +I-472 ++ I-473 +++ I-474 + I-475 ++ I-476 +++ I-477 ++ I-478 ++ I-479 +I-480 + I-481 +++ I-482 ++ I-483 + I-484 +++ I-485 ++ I-486 + I-487 +I-488 ++ I-489 ++ I-490 +++ I-491 ++ I-492 ++ I-493 ++ I-494 + I-495 +++I-496 + I-497 + I-498 ++ I-499 +++ I-500 + I-501 + I-502 ++ I-503 ++I-504 +++ I-505 + I-506 ++ I-507 + I-508 +++ I-509 + I-510 +++ I-511 +++I-512 + I-513 + I-514 + I-515 + I-516 +++ I-517 + I-518 ++ I-519 + I-520++ I-521 +++ I-522 +++ I-523 ++ I-524 ++ I-525 ++ I-526 ++ I-527 ++I-528 ++ I-529 +++ I-530 ++ I-531 ++ I-532 ++ I-533 +++ I-534 + I-535 +I-536 + I-537 +++ I-538 ++ I-539 ++ I-540 +++ I-541 + I-542 +++ I-543+++ I-544 +++ I-545 +++ I-546 +++ I-547 +++ I-548 ++ I-549 + I-550 +I-551 ++ +++ for IC₅₀ < 10 nM; ++ for IC₅₀ in 10 nM-100 nM range; + forIC₅₀ 100 nM-1 μM.

Example 18: GCN2 Cellular Inhibition Assay

Compounds can be screened for their ability to inhibit intracellularGCN2 using an AlphaScreen assay (Perkin Elmer) to detect phosphorylationof the GCN2 substrate eIF2α in borrelidin-treated cells. U2OS cells areplated at 5,000 cells per well in 384-well white polystyrene plates(Corning 3570) in McCoy's 5A media (GIBCO 26600-023) supplemented with10% foetal bovine serum (SAFC 12103C), Penicillin/Streptomycin solutiondiluted 1:100 (Sigma P0781), and 2 mM L-glutamine (Sigma G7513), andallowed to adhere overnight at 37° C. in 5% CO₂. Compounds are thenadded to the cell media from a final concentration of 40 μM in 4-foldserial dilutions. Borrelidin (FluoroChem M01440) is immediately added tothe wells to a final concentration of 10 μM and the cells are incubatedfor 1 h at 37° C. in 5% CO₂. After 1 h of treatment with borrelidin, themedia is removed, and the cells are lysed with lysis buffer (TGRBioSceinces TGRLB) at ambient temperature.

An AlphaScreen SureFire P-eIF2α (Ser51) assay kit (Perkin ElmerTGREIF2S) was used to measure levels of eIF2α phosphorylated on Serine51. Anti-phosphorylated eIF2α Ser51 antibody-linked acceptor beads (TGRBioScience 6760617) are added to the cell homogenate (diluted 1:250 intoa mixture of activation (TGR BioScience TGRAB) and reaction buffer (TGRBioScience TGREIF2S) prepared immediately before use). The plate is thenincubated for 2 h at ambient temperature in the dark. Anti-eIF2αantibody-linked donor beads (TGR BioScience 6760617) were then added(diluted 1:100 in dilution buffer (TGR BioScience TGRDB) preparedimmediately before use). The plate is then incubated overnight atambient temperature in the dark.

Plates are analyzed on an Alpha Technology-compatible PHERAstar FS platereader (BMG Labtech Version 1.14) to quantify phosphorylated eIF2α Ser51levels. The percentage inhibition of phosphorylated eIF2α is calculatedby comparison to control wells stimulated with borrelidin alone. Thesedata are plotted against concentration of compound and IC₅₀ aredetermined using Genedata Analyzer (Genedata AG Version 12.0.3).

TABLE 5 Cellular activity for compounds of formula I (biomarker assay)GCN2 Biomarker Compound (IC₅₀) I-1 ++ I-2 +++ I-3 +++ I-4 ++ I-5 ++ I-6++ I-8 ++ I-9 +++ I-10 +++ I-11 + I-12 +++ I-13 ++ I-14 ++ I-15 +++ I-16++ I-17 +++ I-18 +++ I-19 ++ I-20 +++ I-21 ++ I-22 +++ I-23 +++ I-24 +++I-25 ++ I-27 +++ I-28 ++ I-29 + I-31 ++ I-32 ++ I-33 + I-34 +++ I-35 ++I-36 +++ I-37 +++ I-39 +++ I-41 ++ I-42 ++ I-43 ++ I-44 +++ I-45 +++I-46 ++ I-47 ++ I-48 +++ I-49 + I-50 ++ I-54 ++ I-55 ++ I-56 ++ I-57 ++I-58 ++ I-59 + I-62 ++ I-63 +++ I-65 ++ I-66 ++ I-76 + I-77 + I-81 ++I-83 ++ I-84 + I-85 + I-86 ++ I-88 +++ I-90 +++ I-92 ++ I-102 +++ I-103+++ I-104 ++ I-105 + I-106 + I-107 +++ I-108 +++ I-109 ++ I-110 ++ I-111++ I-112 ++ I-113 ++ I-114 +++ I-115 +++ I-116 ++ I-117 +++ I-118 +++I-120 +++ I-123 +++ I-124 +++ I-125 +++ I-126 +++ I-127 +++ I-128 +++I-130 ++ I-134 +++ I-135 +++ I-136 +++ I-137 +++ I-138 +++ I-143 +++I-144 +++ I-145 +++ I-146 ++ I-147 +++ I-148 +++ I-149 +++ I-150 +++I-153 +++ I-154 +++ I-157 +++ I-159 +++ I-169 ++ I-170 +++ I-171 +++I-172 +++ I-175 +++ I-176 +++ I-177 +++ I-179 +++ I-180 +++ I-181 ++I-182 +++ I-183 +++ I-184 +++ I-185 +++ I-186 +++ I-191 +++ I-193 +++I-196 +++ I-197 +++ I-198 ++ I-199 +++ I-200 +++ I-201 ++ I-202 +++I-203 ++ I-204 ++ I-208 +++ I-209 +++ I-213 ++ I-217 ++ I-218 ++ I-219++ I-220 ++ I-221 +++ I-222 +++ I-223 +++ I-224 +++ I-225 ++ I-226 ++I-227 ++ I-232 ++ I-233 ++ I-235 +++ I-236 +++ I-238 ++ I-240 ++ I-241++ I-242 + I-244 ++ I-245 ++ I-246 ++ I-247 +++ I-248 +++ I-249 +++I-250 +++ I-251 ++ I-252 ++ I-259 +++ I-260 +++ I-261 +++ I-262 + I-263++ I-266 +++ I-267 ++ I-268 ++ I-269 ++ I-270 +++ I-271 +++ I-272 +++I-273 +++ I-274 ++ I-275 ++ I-277 ++ I-278 +++ I-279 ++ I-280 +++ I-281+++ I-283 ++ I-284 + I-285 ++ I-286 ++ I-287 +++ I-288 +++ I-289 ++I-290 ++ I-291 ++ I-293 +++ I-294 + I-295 ++ I-297 ++ I-298 + I-300 ++I-301 ++ I-302 +++ I-303 ++ I-304 ++ I-307 ++ I-308 ++ I-310 +++ I-311++ I-313 ++ I-314 +++ I-315 +++ I-316 +++ I-317 ++ I-318 + I-320 ++I-321 ++ I-322 +++ I-323 ++ I-324 + I-325 ++ I-326 +++ I-327 ++ I-329+++ I-339 ++ I-340 +++ I-342 +++ I-343 ++ I-344 ++ I-345 ++ I-346 +++I-347 ++ I-348 +++ I-349 ++ I-351 +++ I-352 ++ I-353 +++ I-354 +++ I-355++ I-356 ++ I-357 +++ I-358 +++ I-359 +++ I-360 +++ I-361 ++ I-362 +++I-363 ++ I-363 ++ I-364 + I-365 ++ I-366 +++ I-368 ++ I-369 +++ I-370+++ I-371 ++ I-372 ++ I-373 +++ I-383 ++ I-384 +++ I-385 ++ I-386 ++I-387 ++ I-388 + I-389 ++ I-390 +++ I-391 ++ I-392 ++ I-393 ++ I-395 ++I-396 + I-397 ++ I-398 ++ I-399 ++ I-400 ++ I-401 ++ I-402 ++ I-403 ++I-404 ++ I-405 ++ I-406 ++ I-407 ++ I-408 ++ I-409 +++ I-413 + I-414 ++I-416 ++ I-417 + I-418 ++ I-419 ++ I-420 ++ I-421 + I-422 + I-423 +I-424 ++ I-426 ++ I-440 + I-441 + I-442 ++ I-443 ++ I-444 ++ I-445 ++I-446 ++ I-447 ++ I-448 ++ I-449 +++ I-450 +++ I-461 +++ I-464 ++ I-470+++ I-472 +++ I-473 +++ I-476 +++ I-477 +++ I-478 +++ I-481 +++ I-490+++ I-491 +++ I-492 ++ I-493 +++ I-494 ++ I-495 +++ I-499 +++ I-500 ++I-501 ++ I-502 +++ I-503 +++ I-504 +++ I-505 + I-506 ++ I-507 ++ I-508+++ I-510 +++ I-511 +++ I-512 ++ I-516 +++ I-517 ++ I-520 +++ I-521 +++I-522 +++ I-523 +++ I-524 ++ I-525 ++ I-526 +++ I-527 ++ I-528 +++ I-529+++ I-530 ++ I-531 +++ I-532 ++ I-533 +++ I-536 ++ I-537 +++ I-538 ++I-540 +++ I-541 ++ I-543 +++ I-544 +++ I-545 +++ I-546 +++ I-552 +++I-553 +++ I-554 +++ I-556 ++ +++ for IC₅₀ < 0.5 μM; ++ for IC₅₀ in 0.5μM-5 μM range; and + for IC₅₀ > 5 μM.

Example 19:4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,I-484

To a solution of4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamideI-451 (49.00 mg; 0.13 μmmol; 1.00 eq.) and1-ethoxycyclopropoxy)trimethylsilane (0.13 ml; 0.66 mmol; 5.00 eq.) inmethanol (2.50 ml; 61.72 mmol; 468.32 eq.) was added acetic acid (0.06ml; 1.05 mmol; 8.00 eq.) and then sodium cyanoborohydride (66.25 mg;1.05 mmol; 8.00 eq.). Reaction was allowed to stir overnight at 70° C.and purified with pre-HPLC (10-90% ACN/NH₄OH—H₂O in 12 min) to afford4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide(17.6 mg, 31%) as a white solid.

Example 20:5,5-Difluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid amide, I-202

In a microwave vial containing5,5-Difluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid methyl ester (118.23 mg; 0.27 mmol; 1.00 eq.) was added ammonia 7Nin MeOH (2.00 ml). The reaction was stirred at 100° C. for 72 h beforeit was purified with pre-HPLC (10-90% ACN/0.10% NH4OH—H2O in 12 min) toafford5,5-Difluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylicacid amide (2.2 mg, 1.9%) as a white solid.

Example 21:3-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridineI-127 and(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholineI-126

Step 1:2-Methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholine.A solution of2-chloro-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(200 mg, 0.60 mmol, 1 equiv, 90%),2-methyl-6-(1H-pyrazol-4-yl)morpholine (112.0 mg, 0.60 mmol, 1 equiv,90%) and DIPEA (155.8 mg, 1.21 mmol, 2 equiv, 95%) in i-PrOH (10 mL,124.30 mmol, 206.24 equiv, 95%) was stirred for 16 h at 100 degreesCelsius under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel columnchromatography, eluted with hexane/EtOAc (1:1) to afford2-methyl-6-(1H-pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholine(100 mg, 34.77%) as a white solid.

Step 2:3-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridineand(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholine.The racemic mixture of2-methyl-6-(1H-pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholinewas purified by Chiral-Prep-HPLC with the following conditions(Prep-HPLC-032): Column, Chiralpak IA, 2*25 cm, 20 um; mobile phase, Hex(8 mmol/L NH3.MeOH)—HPLC and IPA-HPLC (hold 15% IPA-HPLC in 29 min);Detector, UV 254/220 nm. Two pure compounds were obtained: Peak 13-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridineI-127, retention time=18.029 min, 10.6 mg (22%), white solid; Peak 2(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}morpholineI-126, retention time=25.76 min, 12.3 mg (25%), white solid.

Example 22:3-{4-[(S)-4-(3-Methanesulfonyl-cyclobutyl)-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridineI-495 and3-{4-[(R)-4-(3-Methanesulfonyl-cyclobutyl)-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridineI-490

Step 1:4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine.To a stirred mixture of4-chloro-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(600.00 mg, 1.808 mmol, 1.00 equiv, 90%) and2-(1H-pyrazol-4-yl)piperazine (458.67 mg, 2.712 mmol, 1.50 equiv, 90%)in i-PrOH (15.00 mL, 245.293 mmol, 271.32 equiv, 95%) were added DIEA(491.98 mg, 3.616 mmol, 2.00 equiv, 95%) dropwise at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 3 h at100° C. under nitrogen atmosphere. Desired product could be detected byLCMS. The resulting mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH2Cl2/MeOH (8:1) to afford4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(510 mg, 61.26%) as a light yellow oil.

Step 2:4-[4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-yl]pyrimidine.To a stirred mixture of4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(100.00 mg, 0.217 mmol, 1.00 equiv, 90%) and3-methanesulfonylcyclobutan-1-one (169.38 mg, 1.086 mmol, 5.00 equiv,95%) in MeOH (2.50 mL, 74.121 mmol, 270.09 equiv, 95%) were addedCH₃COOH (109.83 mg, 1.737 mmol, 8.00 equiv, 95%) and NaBH₃CN (57.47 mg,0.869 mmol, 4.00 equiv, 95%) in portions at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 3 h at 70° C.under nitrogen atmosphere. Desired product could be detected by LCMS.The crude product (110 mg) was purified by Prep-HPLC with the followingconditions (2# SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBDColumn, 30*150 mm, 5 um; mobile phase, Water (10 MMOL/L NH4HCO3+0.1%NH3.H2O) and ACN (30% PhaseB up to 35% in 8 min); Detector, UV 254 nm.80 mg racemic product was obtained. The racemic product (80) mg wasresolved by Chiral-Prep-HPLC with the following conditions(Prep-HPLC-032): Column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 um; mobilephase, Hex (8 mmol/L NH3.MeOH)- and EtOH— (hold 50% EtOH— in 17 min);Detector, UV 254 nm. This resulted in Peak 1: of 4-[(3S)-4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(11.0 mg 9.08%) as a white solid, retention time=4.501 min, ee: 99; Peak2:4-[(3R)-4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(12.1 mg, 9.17%) as a white solid, retention time=5.529 min, ee: 98.

Example 23:4-[4-({6-oxaspiro[2.5]octan-1-yl}methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidineI-476

To a microwave vial containing a solution of4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(50.00 mg; 0.12 mmol; 1.00 eq.) and 6-oxaspiro[2.5]octane-1-carbaldehyde(84.57 mg; 0.60 mmol; 5.00 eq.) in methanol (2.50 ml; 61.72 mmol; 640.56eq.), was added acetic acid (0.01 ml; 0.24 mmol; 2.00 eq.) and thensodium cyanoborohydride (30.33 mg; 0.48 mmol; 4.00 eq.). Reactionallowed to stir overnight at 70 C. LCMS-3 showed desired product masswith full conversion. Reaction was allowed to cool, then diluted withDCM. The reaction was then added drop wise to sat. NaHCO₃ and washed 3times with NaHCO₃ and twice with brine. The organic layer was dried withanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude wasdissolved in DMSO then purified PuriFlash PF-C18HP 15 uL 10-90% MeCN inwater (0.1% Formic Acid) 14 min gradient, then 90% for 3 min. The purefractions were combined and lyophilized to afford the product:4-[4-({6-oxaspiro[2.5]octan-1-yl}methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(46.60 mg; 0.09 mmol)

Example 24:4-[2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine, I-322

To a solution of4-[2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine(150.00 mg; 0.35 mmol; 1.00 eq.), oxetan-3-one (30.28 mg; 0.42 mmol;1.20 eq.) and acetic acid (210.26 mg; 3.50 mmol; 10.00 eq.) in THF (3ml) was treated with sodium triacetoxyborohydride (742.07 mg; 3.50 mmol;10.00 eq.) and the mixture was stirred at room temperature forovernight. LCMS-3 showed that the desired product was observed. Thecrude product was loaded at reverse phase HPLC and purified with 20% ACNin Water containing 0.1% NH₄OH to 100% ACN in 10 minutes at the flowrate of 60 mL/minute to provide the product4-[2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine in 16% yield. M/z (M+H): 485; HNMR (DMSO-d6): 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H),7.57 (1H), 7.46 (1H), 6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42(1H), 1.13 (3H)

Example 25: Exemplary Compounds I-122 to I-563

Additional compounds were prepared using similar methodologies to thosedescribed in the examples above:

-   6-Chloro-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-122-   Dimethyl(((3R,5S)-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-123-   3-{4-[(2S,6R)-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-2-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine,    I-124-   (2R,6S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-125-   (((3R,5S)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-128-   (2R,6    S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-129-   N,N-dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-130-   pyrrolidin-1-yl(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanone,    I-131-   5-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-azaspiro[2.5]octane-1-carboxamide,    I-132-   methyl    5-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-azaspiro[2.5]octane-1-carboxylate,    I-133-   (2S,6S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-134-   (2R,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-135-   3-(2-((3R,5R)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-136 (after chiral separation).-   3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-137 (after chiral separation).-   (2S,6R)-2-methyl-6-(1H-pyrazol-3-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-138-   3-(2-((3R,5S)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-139-   3-(2-((3S,5R)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-140-   3-(2-((3S,5S)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-141-   3-(2-((3R,5R)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-142-   3-(2-((3R,5R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-143-   3-(2-((3R,5S)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-144-   3-(2-((3S,5R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-145-   3-(2-((3S,5S)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-146-   (2 S,6    S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-147-   (3R,5S)-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-148-   5-Methyl-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid amide, I-149-   (S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-150-   (R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-151-   (R)-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-carboxamide,    I-152-   (S)-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-carboxamide,    I-153-   (S)-1-[2-(6-Trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid amide, I-154-   (2R,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifuoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-155-   (2S,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-156-   (2R,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-157-   (2S,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-158-   (((3R,5S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-159-   4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)morpholine,    I-160-   2-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetic    acid, I-161-   2-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide,    I-162-   4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-163-   (R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-164-   2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetic    acid, I-165-   2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide,    I-166-   (((3    S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-167-   (((3    S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-168-   dimethyl(((3    S,5R)-5-methyl-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-169-   3-(2-((2S,5S)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-170-   3-(2-((2R,5R)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-171-   3-(2-((2S,5S)-2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-172-   3-(2-((2R,5R)-2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-173-   (S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)piperidine-3-carboxamide,    I-174-   (2S,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)-6-methylmorpholine,    I-175-   (2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)-6-methylmorpholine,    I-176-   (2S,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholine-2-carboxamide,    I-177-   (2R,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholine-2-carboxamide,    I-178-   (2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-179-   (2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-180-   (2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-181-   (2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-182-   (S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-carboxamide,    I-183-   6-chloro-3-(5-methyl-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-184-   6-chloro-3-(5-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-185-   6-chloro-3-(5-methyl-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-186-   N-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide,    I-187-   4-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-4-carboxamide,    I-188-   (2S,6S)-2-methyl-6-(2H-tetrazol-5-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-189-   (2R,6R)-2-methyl-6-(2H-tetrazol-5-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)morpholine,    I-190-   (((3 S,    5R)-1-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-191-   3-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-192-   3-(4-(2-(5-(difluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile,    I-193-   6-chloro-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-195-   6-chloro-3-(2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-196-   6-chloro-3-(5-methyl-2-((3 S,    5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-197-   6-chloro-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-198-   6-chloro-3-(2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-199-   6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-200-   6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic    acid, I-201-   (2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-203-   (2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-204-   5,5-Difluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid, I-205-   5-fluoro-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic    acid, I-206-   tert-butyl    2-carbamoyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate,    I-207-   6-chloro-3-(6-methyl-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-208-   6-chloro-3-(6-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-209-   6-chloro-3-(6-methyl-2-((3 S,    5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-210-   6-chloro-3-(6-methyl-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-211-   tert-butyl    3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylate,    I-212-   3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-213-   3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic    acid, I-214-   4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-217-   (2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-218-   (S)-1-(5-fluoro-4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-carboxamide,    I-219-   (2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-220-   (2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-221-   (2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-222-   (R)-1-(5-fluoro-4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidine-3-carboxamide,    I-223-   3-(4-(3,3-difluoropiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-224-   2-(difluoromethyl)-4-(2-(6-(trifluoromethyl)imidazo[12-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-225-   3-(4-(3-fluoro-3-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-226-   (S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carbonitrile,    I-227-   1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)azetidine-3-carboxamide,    I-228-   5-fluoro-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-229-   2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)azetidin-3-yl)acetamide,    I-230-   3-(4-(3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-231-   (S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carbonitrile,    I-232-   (S)-6-(trifluoromethyl)-3-(4-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-233-   3-(4-(3,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-234-   6-cyclopropyl-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-235-   6-cyclopropyl-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-236-   tert-butyl ((3    S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)carbamate,    I-237-   (3R,5S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3,5-diol,    I-238-   (3    S,5S)-5-amino-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol,    I-239-   3-(4-((3R,4R)-3-fluoro-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-240-   3-(hydroxymethyl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol,    I-241-   1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-sulfonamide,    I-242-   tert-butyl    ((3R,4R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypiperidin-3-yl)carbamate,    I-243-   (((3    S,5R)-1-(4-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-244-   4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-(3,3,3-trifluoropropyl)piperazine-2-carboxamide,    I-245-   (2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-246-   6-Chloro-3-{2-[(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-imidazo[1,2-a]pyridine,    I-247-   6-Chloro-3-{2-[(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-imidazo[1,2-a]pyridine,    I-248-   6-Cyclopropyl-3-{2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-4-yl}-imidazo[1,2-a]pyridine,    I-249-   6-Cyclopropyl-3-{2-[(3    S,5S)-3-methyl-5-(1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-4-yl}-imidazo[1,2-a]pyridine,    I-250-   (2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-251-   tert-butyl    ((3R,5R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)carbamate,    I-252-   2-hydroxy-N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide,    I-253-   2-hydroxy-N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propanamide,    I-254-   (3R,4R)-3-amino-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol,    I-255-   (3R,5R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-amine,    I-256-   N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazole-4-carboxamide,    I-257-   1-(2-methoxyethyl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-258-   6-(3,3-difluoroazetidin-1-yl)-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-259-   (R)-1-(3-fluoro-6-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide,    I-260-   6-(3,3-difluoroazetidin-1-yl)-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-261-   3-(4-((3S,5R)-3-((dimethyl(oxo)-λ6-sulfaneylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile,    I-262-   1-(oxetan-3-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-263-   (2S,6S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-264-   (2S,6R)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-265-   6-chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-266-   6-chloro-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-267-   6-chloro-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-268-   (((3    S,5R)-1-(2-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-269-   (2S,6R)-4-(4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-270-   6-(azetidin-1-yl)-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-271-   6-(azetidin-1-yl)-3-(2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-272-   (2R,6S)-4-(4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-273-   (2R,6R)-4-(4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-274-   (2S,6S)-4-(4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-275-   1-(4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)piperazin-1-yl)ethan-1-one,    I-276-   1-(4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)piperazin-1-yl)ethan-1-one,    I-277-   (S)-1-(5-fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-278-   6-chloro-3-(6-methoxy-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-279-   6-chloro-3-(6-methoxy-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-280-   6-chloro-3-(6-methoxy-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-281-   (S)-1-(5-fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-282-   N-((1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-N-methylmethanesulfonamide,    I-283-   2-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-2-methylpropanoic    acid, I-284-   tert-butyl    6-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate,    I-285-   4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-286-   6-(3,3-difluoroazetidin-1-yl)-3-(6-methyl-2-((3 S,    5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-287-   6-(3,3-difluoroazetidin-1-yl)-3-(6-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyridine,    I-288-   (((3    S,5R)-1-(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-289-   dimethyl(((3    S,5R)-5-methyl-1-(2-(6-(trifluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-290-   dimethyl(((3    S,5R)-5-methyl-1-(2-(6-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-291-   tert-butyl    6,6-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate,    I-292-   (2R,6    S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-293-   6,6-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane,    I-294-   (R)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one,    I-295-   (S)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one,    I-296-   1-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)cyclopropane-1-carboxylic    acid, I-297-   2-(4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetic    acid, I-298-   6-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane,    I-299-   (((3    S,5R)-1-(2-(6-cyclopropylimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-300-   6-chloro-3-(4-(3-methyl-4-(methyl sulfonyl)-5-(1-(methyl    sulfonyl)-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-301-   1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol,    I-302-   1-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)cyclopropane-1-carboxamide,    I-303-   6,6-dimethyl-2-(methylsulfonyl)-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane,    I-304-   2-((6,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methoxy)-N,N-dimethylacetamide,    I-305-   (3 S,    5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol,    I-307-   (3R,5S)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol,    I-308-   2-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-2-methylpropanamide,    I-309-   3-(4-((3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-310-   1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-311-   dimethyl(((3R,5S)-5-methyl-1-(2-(6-(methyl    sulfonyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-312-   3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(methylsulfonyl)imidazo[1,2-a]pyridine,    I-313-   (3    S,5S)-5-(3-Methyl-1H-pyrazol-4-yl)-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-ol    I-314.-   (3R,5R)-5-(3-Methyl-1H-pyrazol-4-yl)-1-[2-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-ol    I-315-   (3    S,5S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-hydroxypiperidine-3-carboxamide,    I-316-   (((3    S,5R)-1-(2-(6-bromo-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-317-   3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-N-cyclopropylimidazo[1,2-a]pyridine-6-sulfonamide,    I-318-   N-cyclopropyl-3-(4-((3R,5S)-3-((dimethyl(oxo)-λ6-sulfaneylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide,    I-319,-   3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide,    I-320-   3-(4-(2-methyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-321-   (R)-1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-323-   (S)-1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazzo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-324-   dimethyl({[(3    S,5R)-5-methyl-1-(2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-yl]imino})-λ6-sulfanone    I-325-   3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromo-7-fluoroimidazo[1,2-a]pyridine,    I-326-   N-(1-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide,    I-327-   3-(4-((3R,5S)-3-((dimethyl(oxo)-λ6-sulfaneylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide,    I-328-   2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}-4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine    I-329-   (((3    S,5R)-1-(2-(6-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-330-   6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carbonitrile,    I-331-   3-methyl-5-(1-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)-1,2,4-oxadiazole,    I-332-   3-(4-(3,3-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-333-   3-(4-(3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-334-   3-(4-(4-(2-methoxyethyl)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-335-   1-(2,2-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one,    I-336-   3-(4-(3-(5-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-337-   8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)octahydropyrazino[2,1-c][1,4]thiazine    2,2-dioxide, I-338-   3-(4-(3,3-dimethyl-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-339-   (((3 S,    5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-340-   (2S,6S)-4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholine,    I-341-   dimethyl(((3R,5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-342-   (2R,6R)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-343-   dimethyl(((3    S,5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone,    I-344-   (2S,6S)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-345-   (2S,6R)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-346-   (2R,6S)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-347-   3-(4-(4-(1-ethoxycyclopropyl)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-348-   (R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-349-   (s)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-350-   3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-351-   3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propane-1,2-diol,    I-352-   4-((2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)oxazole,    I-353-   3-(4-(3-(1H-pyrazol-4-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-354-   6-(trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-355-   3-(4-(3-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-356-   3-(4-(3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-357-   2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-358-   (2S,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)morpholine,    I-359-   (2R,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)morpholine,    I-360-   3-(4-((2S,3R)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-361-   4-[(2R,3    S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-362-   3-(4-((2R,3R)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-363-   3-(4-((2S,3    S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-364-   3-(4-(2    S,3R)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-365-   3-(4-(2R,3    S)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-366-   3-(4-(2 S,3    S)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-367-   3-(4-(2R,3R)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-368-   4-[4-(cyclopropylmethyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-369-   3-(4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-370-   3-(4-(4-((1H-imidazol-2-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-371-   3-(4-(4-((2-methyl-1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-372-   3-(4-(4-((2-(tert-butyl)-1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-373-   3-(4-(4-(oxetan-3-ylmethyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-374-   (2R,6R)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholine,    I-375-   (((3 S,    5R)-1-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-376-   6-cyclopropyl-7-fluoro-3-(4-(3-fluoro-5-(5-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-377-   4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,    I-378-   3-(4-(3-methyl-4-(1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-379-   3-methyl-4-{2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl}piperazine-2-carboxamide,    I-380-   (1-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)methanol,    I-382-   3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)cyclobutan-1-ol,    I-383-   3-(4-(4-((1-methyl-1H-pyrazol-4-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-384-   3-(4-(4-((1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-385-   tert-butyl    8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate,    I-386-   tert-butyl    6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate,    I-387-   tert-butyl    9,9-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate,    I-388-   4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-389-   (3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)cyclobutyl)methanol,    I-390-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-isopropyl-1H-pyrazol-4-yl)methanone,    I-391-   3-(4-(4-cyclopropyl-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-392-   2-(2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)acetonitrile,    I-393-   N-(((1R,4S)-2-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-azabicyclo[2.2.2]octan-6-yl)methyl)methanesulfonamide,    I-394-   6-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane,    I-395-   8-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6,6-dimethyl-2-(methyl    sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane, I-396-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(cyclopropyl)methanone,    I-397-   2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}-4-[(3R)-3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine    I-398-   2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl)}-4-[(3    S)-3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine I-399-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(2,2-difluorocyclopropyl)methanone,    I-400-   (cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[12-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-isopropyl-1H-pyrazol-3-yl)methanone,    I-401-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(3,3-difluorocyclobutyl)methanone,    I-402-   cyclopropyl(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-403-   N—((R)-1-((S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide,    I-404-   N—((S)-1-((R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide,    I-405-   N—((R)-1-((R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide,    I-406-   N—((S)-1-((S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide,    I-407-   3-(4-((3R,5S)-3-methyl-5-(5-methyl-2H-1,2,3-triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-408-   3-(4-((3S,5R)-3-methyl-5-(5-methyl-2H-1,2,3-triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-409-   3-(4-(cis-3,5-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-410-   tert-butyl    3-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate,    I-411-   8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane,    I-412-   6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane,    I-413-   1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one,    I-414-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methanone,    I-415-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-(2-methoxyethyl)-1H-pyrazol-4-yl)methanone,    I-416-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-(oxetan-3-yl)-1H-pyrazol-4-yl)methanone,    I-417-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone,    I-418-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanone,    I-419-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxypropan-1-one,    I-420-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxyethan-1-one,    I-421-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-(1H-imidazol-1-yl)propan-1-one,    I-422-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-one,    I-423-   (S)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-424-   (R)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide,    I-425-   6-chloro-7-fluoro-3-(4-(3-fluoro-5-(5-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-426-   4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,    I-427-   (2S,6S)-4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-428-   (2S,6R)-4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-429-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carbonyl)cyclopropane-1-carbonitrile,    I-432-   (R)-1-(4-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)-1H-pyrazole-1-carbonyl)cyclopropane-1-carbonitrile,    I-433-   (2R,3R)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-434-   (2S,3    S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-2-carboxamide,    I-435-   N-(((2R,3    S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-436-   (3,3-difluorocyclobutyl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-437-   (2,2-difluorocyclopropyl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-438-   3-(4-(cis-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-439-   (1-cyclopropyl-1H-pyrazol-3-yl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-440-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1,2,5-oxadiazol-3-yl)methanone,    I-441-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(2H-1,2,3-triazol-4-yl)methanone,    I-442-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(oxazol-4-yl)methanone,    I-443-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(isoxazol-4-yl)methanone,    I-444-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1H-imidazol-4-yl)methanone,    I-445-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone,    I-446-   2-(methylsulfonyl)-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane,    I-447-   2-(methylsulfonyl)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane,    I-448-   3-(4-(3-(1H-pyrazol-4-yl)-4-(3,3,3-trifluoropropyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-449-   3-(4-(4-(3,4-difluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-450-   4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,    I-451-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(2-methoxypyridin-4-yl)methanone,    I-452-   (2R,3    S)-4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,    I-454-   4-(2-(6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide,    I-455-   3-(4-(3-(1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-456-   3-(4-(4-(4-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-457-   3-(4-(4-(3-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-458-   3-(4-(4-(2-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-459-   3-(4-(4-(4,4-difluorocyclohexyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-460-   4-{4-[(1,2,5-oxadiazol-3-yl)methyl]-3-(1H-pyrazol-4-yl)piperazin-1-yl}-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-461-   3-(4-(cis-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-462-   3-(2-((3R,5S)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-463-   1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one,    I-464-   3-(2-((3S,5S)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-465-   3-(2-((3S,5R)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-466-   3-(2-((3R,5R)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-467-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(spiro[2.2]pentan-1-yl)methanone,    I-468-   5-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidin-2-one,    I-469-   3-(4-(4-((2,2-difluorocyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-470-   N-(((2 S,3    S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-471-   N-((1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl)methanesulfonamide,    I-472-   3-(4-(4-((2-methyl    cyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-473-   (S)-6-((S)-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carbonyl)piperidin-2-one,    I-474-   3-(4-(3-(1H-pyrazol-4-yl)-4-(spiro[2.2]pentan-1-ylmethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-475-   3-(4-(4-((2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-477-   N-(5-(trifluoromethyl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide,    I-478-   (R)-(1,3-dimethyl-1H-pyrazol-4-yl)(2-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-479-   (S)-(1,3-dimethyl-1H-pyrazol-4-yl)(2-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-480-   3-(4-((2    S,3R)-2-methyl-4-((3-methyloxetan-3-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-481-   3-(4-((2 S,3    S)-2-methyl-4-((3-methyloxetan-3-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-482-   (cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(pyridin-4-yl)methanone,    I-483-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)((1R,2R)-2-fluorocyclopropyl)methanone,    I-485-   (cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-methylcyclopropyl)methanone,    I-486-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone,    I-487-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-(difluoromethyl)cyclopropyl)methanone,    I-488-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)((1R,2R)-2-fluorocyclopropyl)methanone,    I-489-   N-(((2R,3    S,6S)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-491-   4-(2,2-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazine-1-carbonyl)cyclohexan-1-one,    I-492-   N-(((2R,3R,6R)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-493-   N-(((2S,3R,6R)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-494-   N-((4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-(trifluoromethyl)piperazin-2-yl)methyl)methanesulfonamide,    I-496-   (2R,6R)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholine,    I-497-   (2S,6S)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholine,    I-498-   (((3    S,5R)-1-(4-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-499-   N—((S)-1-((2S,3    S)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide,    I-500-   1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-(oxetan-3-yl)ethan-1-one,    I-501-   (S)-3-(4-(3-(1H-pyrazol-4-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-502-   (R)-3-(4-(4-cyclopropyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-503-   (R)-3-(4-(3-(1H-pyrazol-4-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-504-   N—((R)-1-((2R,3R)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide,    I-505-   N—((R)-1-((2 S,3    S)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide,    I-506-   N—((S)-1-((2R,3R)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide,    I-507-   3-{2-[(R)-4-Cyclopropyl-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-6-trifluoromethyl-imidazo[1,2-a]pyridine,    I-508,-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(3-hydroxy-3-methylcyclobutyl)methanone,    I-509-   3-(4-(4-((1-methyl    cyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-510-   4-[(2R,3    S)-4-{[1-(methoxymethyl)cyclobutyl]methyl}-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-511-   4-[(2S,3    S)-4-{[1-(methoxymethyl)cyclobutyl]methyl}-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-512-   (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone,    I-513-   1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one,    I-514-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(5-methylisoxazol-4-yl)methanone,    I-515-   N-(((2R,3    S)-1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl)methanesulfonamide,    I-516-   N-(((2    S,3R)-1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl)methanesulfonamide,    I-517-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(4-methyl-1,2,5-oxadiazol-3-yl)methanone,    I-518-   (2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(3,5-dimethylisoxazol-4-yl)methanone,    I-519-   3-(4-((R)-4-(((R)-6-oxaspiro[2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-520-   3-(4-((S)-4-(((S)-6-oxaspiro[2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-521-   3-(4-((S)-4-(((R)-6-oxaspiro[2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-522-   3-(4-((R)-4-(((S)-6-oxaspiro[2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-523-   ((2S,6S)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methanol,    I-524-   N-(1-(4-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)methanesulfonamide,    I-525-   3-(4-((R)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-526-   3-(4-((S)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-527-   3-(4-((S)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-528-   3-(4-((R)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-529-   N-((4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methyl-1-(oxetan-3-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-530-   N-(1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)methanesulfonamide,    I-531-   (R)-3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-532-   (S)-3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-533-   3-(4-((2    S,3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-534-   3-(4-((2S,3    S)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-535-   3-(4-((2R,3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-536-   4-[(2R,3    S)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine,    I-537-   (2R,6R)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-538-   (2S,6S)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-539-   (2R,6S)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-540-   N-(((2R,3    S)-1-cyclopropyl-3-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperazin-2-yl)methyl)methanesulfonamide,    I-541-   3-(2-((S)-3-(1H-pyrazol-4-yl)-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-542-   N-{(2S,3R)-1-Cyclopropyl-3-methyl-4-[4-(6-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-yl]-piperazin-2-ylmethyl}-methanesulfonamide,    I-543-   3-(2-((R)-3-(1H-pyrazol-4-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-544-   3-(2-((R)-3-(1H-pyrazol-4-yl)-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-545-   3-(2-((S)-3-(1H-pyrazol-4-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-546-   (2R,3R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropyl-3-methylpiperazine-2-carboxamide,    I-547-   (2S,3    S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropyl-3-methylpiperazine-2-carboxamide,    I-548-   (S)-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(5-methylisoxazol-4-yl)methanone,    I-549-   (R)-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(5-methylisoxazol-4-yl)methanone,    I-550-   1-(2-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carbonyl)cyclopropane-1-carbonitrile,    I-551-   3-(4-((R)-3-(1H-pyrazol-4-yl)-4-(((R)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-552-   3-(4-((S)-3-(1H-pyrazol-4-yl)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-553-   3-(4-((S)-3-(1H-pyrazol-4-yl)-4-(((R)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-554-   3-(4-((R)-3-(1H-pyrazol-4-yl)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-555-   (S)-6-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-thiaspiro[3.3]heptane    2,2-dioxide, I-556-   (R)-6-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2-thiaspiro[3.3]heptane    2,2-dioxide, I-557-   (S)-1-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxamide,    I-558-   6-chloro-3-(4-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-559-   (2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-560-   (2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)morpholine,    I-561-   (2S,6S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide,    I-562-   6-chloro-3-(4-((2S,3R,5S)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine,    I-563-   (2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine,    I-564-   3-(4-((2R,3    S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-565-   (2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-566-   3-(4-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine,    I-567-   (2S,6R)-4-(2-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine,    I-568-   (((3R,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone,    I-569

Example 26: Human IL-2 Assay for GCN2 Inhibition

Tumor microenvironment is profoundly immuno-suppressive. This may beattributed to the depletion of amino acids (like arginine andtryptophan) which triggers the activation of GCN2 in immune cells,including T cell and myeloid cells. In T cells, activation of GCN2 leadsto reduce effector functions of CD8 T cells and induction and/ormaintenance of immuno-suppressive T-regs. Inhibition of thatimmuno-suppressive response by GCN2 inhibitors enables an anti-cancerimmune response by activating effector T-cells. Herein we describe anin-vitro system we established using human T-cells stimulated in lowamino acid condition in order to engage the GCN2 biology. The methoddescribed involves the modulation of IL-2 levels secreted by human Tcells in responses to the GCN2 inhibitors disclosed herein.

Amino acid-free RPMI was reconstituted with all but one of the aminoacids found in standard RMPI (e.g. Arginine, Tryptophan), 10%charcoal-stripped fetal bovine serum, 100 Units/mL penicillin and 0.1mg/mL streptomycin. Primary human pan T-cells were isolated using Pan TCell Isolation Kit, human (MACS Miltenyi biotech Cat # Order no.130-096-535) from apheresis cones and 5×104 pan T-cells per well. Thepurified T cells are seeded in Nunc™ 96-Well Polystyrene Round BottomMicrowell Plates (the cells are rested in No TRP media in a 15 ml falcontube in the incubator for 30-45 minutes while titrations for tryptophanand the GCN2 inhibitor compound are made) A plate matrix was developedto titrate both a GCN2 inhibitor and the amino acid of interest rangingfrom “No Amino Acid” condition, up to the concentration found in theregular RPMI media (20 μM for TRP and 950 μM for Arginine). The cellswere incubated for 30 min at 37° C. with the GCN2 inhibitor and thenstimulated with 5×104 anti-CD3/CD28 Dynabeads® per well. After 96 hoursof incubation the IL-2 level in the supernatant were measured usingELISA (R&D systems Cat # DY202 (Human IL-2 DuoSet ELISA). Data wereplotted in GraphPad Prism software and EC₅₀ is calculated.

TABLE 6 EC₅₀ values based on IL-2 secretion from T cells IL2/T-cell EC₅₀Compound I# (nM) I-102 ++ I-116 +++ I-123 +, − I-124 ++, +++ I-125 +++,++, + I-126 ++ I-127 +++ I-128 + I-134 + I-135 ++ I-136 +++, ++ I-137 ++I-148 ++ I-154 +++ I-160 ++ I-170 ++ I-176 +++ I-179 ++ I-185 − I-191 −I-200 ++ I-209 ++ I-223 ++ I-247 +++ I-248 ++ I-249 ++ I-250 − I-259 +++I-293 +++ I-314 − I-315 ++ I-323 + I-354 ++ I-359 ++ I-366 +++ I-409 +I-473 ++ I-481 +++ I-482 + I-495 + I-499 + I-504 ++ I-547 ++ I-558 ++I-559 +++ I-560 +++ I-561 ++ I-562 ++ I-563 ++ I-564 +++ I-565 +++ I-566+++ I-567 +++ I-568 ++ I-569 ++ I-562 ++ +++ for EC₅₀ < 100 nM; ++ forEC₅₀ in the 100-500 nM range; + for EC₅₀ > 500 nM; and “−” for notactive

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of one of formula XV-a, XV-a, or XV-c:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ isindependently hydrogen, halogen, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)NRS(O)₂R, —C(O)N═S(O)R₂, —NR₂, —NRC(O)R, —NRC(O)NR₂, —NRC(O)OR,—NRS(O)₂R, —NRS(O)₂NR₂, —OR, —ON(R)SO₂R, —P(O)R₂, —SR, —S(O)R, —S(O)₂R,—S(O)(NH)R, —S(O)₂N(R)₂, —S(NH₂)₂(O)OH, —N═S(O)R₂, —CH₃, —CH₂OH,—CH₂NHSO₂CH₃, —CD₃, —CD₂NRS(O)₂R, or R; or two R¹ groups are optionallytaken together to form ═O or ═NH; or two R¹ groups are optionally takentogether to form a bivalent C₂₋₄ alkylene chain; each R is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic, a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclicring, a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ringhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; or two R groups are optionally taken together to form a bivalentC₂₋₄ alkylene chain; or two R groups are optionally taken together withtheir intervening atoms to form an optionally substituted 3-7 memberedsaturated or partially unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen or sulfur; m is0, 1, 2, 3, 4 or
 5. 2. The compound of claim 1, wherein m is 1, 2 or 3.3. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 5. Thecompound of claim 1, wherein R¹ is hydrogen, halogen, —CN, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NRS(O)₂R, —C(O)N═S(O)R₂, —NR₂, —NRC(O)R,—NRC(O)NR₂, —NRC(O)OR, —NRS(O)₂R, —NRS(O)₂NR₂, —OR, —ON(R)SO₂R, —P(O)R₂,—SR, —S(O)R, —S(O)₂R, —S(O)(NH)R, —S(O)₂N(R)₂, —S(NH₂)₂(O)OH, —N═S(O)R₂,—CH₃, —CH₂OH, —CH₂NHSO₂CH₃, —CD₃, —CD₂NRS(O)₂R, or R.
 6. The compound ofclaim 1, wherein two R¹ groups are taken together to form a bivalentC₂₋₄ alkylene chain.
 7. The compound of claim 1, wherein two R¹ groupsare taken together to form ═O or ═NH.
 8. The compound of claim 5,wherein each R is independently hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, a 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 9. The compoundof claim 5, wherein R is hydrogen.
 10. The compound of claim 5, whereinR is an optionally substituted C₁₋₆ aliphatic.
 11. The compound of claim5, wherein R is an optionally substituted 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring.
 12. The compound ofclaim 5, wherein R is an optionally substituted phenyl.
 13. The compoundof claim 5, wherein R is an optionally substituted 8-10 memberedbicyclic aromatic carbocyclic ring.
 14. The compound of claim 5, whereinR is an optionally substituted 4-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 15. Thecompound of claim 5, wherein R is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 16. The compound of claim 5,wherein R is an optionally substituted 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 17. The compound of claim 5, wherein two Rgroups are taken together to form a bivalent C₂₋₄ alkylene chain. 18.The compound of claim 5, wherein two R groups are taken together withtheir intervening atoms to form an optionally substituted 3-7 memberedsaturated or partially unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen or sulfur. 19.The compound of claim 1, wherein a R¹ group is selected from the groupconsisting of: fluoro, chloro, methyl, ethyl, —OH, —OCH₃, —CH₂OH,—CH₂CN, —CF₃, —CH₂NH₂, —COOH, —NH₂,


20. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


21. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


22. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


23. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


24. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


25. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


26. The compound of claim 1, wherein a R¹ group is selected from thegroup consisting of:


27. The compound of claim 1, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound according to claim 3, and apharmaceutically acceptable carrier, adjuvant, or vehicle.